\y' 


Digitized  by  the  Internet  Arciiive 

in  2007  witii  funding  from 

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http://www.archive.org/details/experimentalpharOOhermrich 


A  MANUAL 


OF 


EXPERIMENTAL  PHARMACOLOGY. 


\(L 


EXPERIMENTAL  PHARMACOLOGY. 


A  HAND-BOOK 


METHODS  FOR  STUDYING  THE  PHYSIOLOGICAL 
ACTIONS  OF  DRUGS. 

BY 

L.  (HERMANN, 

PROFESSOR  OF  PHYSIOT-OOY  IN  THE  UXIVERSITY  OF  ZURICH. 


TRANSLATED,   WITH    THE  AUTHOR'S    PERMISSION,   WITH  NOTES 
AND  ADDITIONS, 

BY 
ROBERT  MEADE  SMITH,  M.D., 

DEMONSTRATOR    OF    PHYSIOLOGY    IN    THE    UNIVERSITY    OP    PENNSYLVANIA. 


WITH   THIRTY-TWO   ILLUSTRATIONS   ON   WOOD. 


H55-IB 
1883 


PHILADELPHIA: 

HENRY   C.   LEAVS    SON   &   CO 

1883. 


Entered  according  to  the  Act  of  Congress,  in  the  year  1883,  by 

HENRY    C.   LEA'S    SON   &  CO., 
in  the  Office  of  the  Librarian  of  Congress.     All  rights  reserved. 


C  U  L  L  1  X  S  ,     P  R  I  N  '1'  R  R 


TRANSLATOR'S  PREFACE, 


The  translation  of  Hermann's  Manual  of  Pharma- 
cology was  undertaken  to  furnish  the  student  with  a 
work  that  would  assist  him  in  his  studies  of  the  physio- 
logical action  of  drugs,  enabling  him  to  make  the 
experiments  himself  that  would  otherwise  require  the 
assistance  of  the  instructor. 

The  translator  has  attempted  to  elucidate  the  text 
with  a  careful  selection  of  illustrations;  and  he  trusts 
that  his  voluminous  additions,  which  constitute  nearly 
one-half  of  the  entire  volume,  will  render  the  work  a 
more  perfect  guide  to  the  student. 

Frbruary  1,  18S3. 


87766 


TABLE  OF  CONTENTS. 


Intkoductiox. 

PAGE 

Definition  of  a  Poison — Scope  of  Pharmacology — Methods 
of  Study — Methods  of  Pharmacological  Investigation       .       13 


PART  I. 

STUDY  OF  THE  ACTION  OF  A  POISON  ON  ISOLATED 
ORGANS. 


Section  I. — Action  on  the  Blood 

1.  Alterations  in  the  Consistence  of  the  Blood     . 

2.  Alterations  in  the  Reaction  of  the  Blood 

3.  Alterations  in  the  Red  Blood-Corpuscles 

4.  Alterations  in  the  White  Corpuscles 

5.  Alterations  in  the  Coagulability  of  the  Blood  . 

6.  Alterations  in  the  Coloring  Matter  of  the  Blood 

7.  Alterations  in  the  Gases  of  the  Blood  and  in  the 

Power  of  Absorbing  Gases  .... 

8.  Alterations  in  the  Ozone  and  Ozonizing  Power  of 

the  Blood 

Section  II. — Action  on  the  Muscles     . 

1.  Examination  of  Indirect  Muscular  Irritability 

2.  Examination  of  Direct  Muscular  Irritability    . 

3.  Examination  of  the  Physiological  Conductivity  of 

Muscle 

4.  Measurement  of  Muscular  Energy  . 

5.  Examination  of  Alterations  in  the  Chemical  Proper 

ties  of  Muscle     ...... 

Section  III.— Action  on  the  Nerves     . 
Section  IV. — Action  on  the  Heart 


20 
23 
23 
25 
28 
29 
29 

30 

30 
31 
37 
46 

47 

48 

48 
49 
52 


Vlll  TABLE    OF    CONTE^^TS. 


PART  11. 


INVESTIGATION  OF  THE  UENERAL  ACTION  OF  POISONS. 

PAGE 

I. — Selection  of  Animals 55 

Section  I. — Modes  of  Securing  Animals      ...       60 

II. — Administration  of  Poisons 63 

Section  I. — Injection  into  the  Bloodvessels     .         .       65 

Section  II. — Subcutaneous  Injections  and  Injec- 
tions into  Serous  Sacs,  Lymph  Sacs  of  the  Frog, 
ETC 70 

Section  III. — Insertion  of  Poisons  into  the  Mucous 
Cavities  of  the  Body 70 

Section  IV. — Administration  of  Gases  and  Vapors 

THROUGH  THE  LlTNGS     .......  73 

III. — Investigation  of  the  Paths  of  Elimination 
and  Changes  of  Poisons  in  the  Body     .         .         .       77 

Section  I. — Passage  of  Drugs  through  the  System 

without  Change         .         .         .         .'       .         .         .78 
Section  II. — Deposit  of  Drugs  in  the  System  through 

Assimilation 80 

Section  III. — Chemical  Alteration  of  Poisons  in  the 
Economy      .........       80 

a.  Displacement  of  Acids  or  Bases  in  vSalts  .  .       81 

h.   Formation  of  Chemical  Compounds  with  Innjredients 
of  the  Tissues  and  Excretion  under  Modified  Forms       82 

c.  Decomposition  of  Poisons  in  the  System  and  Excre- 
tion of  the  Decomposition  Products  ....       82 

d.  Decomposition  of  Poisonous  Substances  and  Excre- 
tion of  their  Products       ......       84 

IV. — Explanation  of  the  Symptoms  produced  by 
Poisons 85 

Section  I. — Action  on  the  Circulatory  Apparatus  .       88 
Mode  of  Conducting  an  Experiment  on  Blood- Pressure       92 


TABLE    OF    CONTENTS.  IX 

PAGE 

Causes  of  Changes  in  the  Ch'cuhitory  Mechanism  .      105 

The  Cardiac  Ganglia 106 

The  Cardiac  Inhibitory  Nerves    .         .         .         .         .107 
The  Accelerator  Nerves       .         .         .         .         .         ,108 

The  Vaso-Motor  System 110 

Indirect  Results  of  Circulatory  Disturbances         .         .128 

Section  II. — Action  on  the  Respiratory  Apparatus     130 

a.  Dyspnoea        .  .  .  .  .  .  .  .131 

h.   Cessation  of  Respiratory  Movements       .         .         .134 

1.  Reduction  of  the  Respiratory  Stimulus  through 
Saturation  of  the  Blood  with  Oxygen,  and  Diminu- 
tion of  its  Carbon  Di-oxide  .         .         .         .         ,134 

2.  Reduction  in  Irritability  of  the  Respiratory  Centre     134 


3.  Paralysis  of  the  Respiratory  Muscles 

c.  Alterations  in   the   Frequency  of   the  Respiratory 

Movements  ....... 

d.  Appearances  in  the  Larynx     .... 
Section  III. — Action  on  the  Digestive  Apparatus 

a.   Alterations   in   the    Movements   of    the    Digestive 
Organs         .         .         ,         , 

1 .  Movements  of  the  Jaws 

2.  Deglutition 

3.  Movements  of  the  Stomach 

4.  Movements  of  the  Intestines 
h.  Alterations  in  the  Sensibility  of,  and  Production  of 

Abnormal  Sensations  in  the  Alimentary  Canal 

c.  Alterations  in  the  Digestive  Secretions     . 

d.  Alteration  in  the  Digestive  Processes 
Section  IV. — Action  on  Glandular  Organs 

a.  Secretory  Glands    ...... 

1.  Action  on  the  Salivary  Secretion 

2.  Action  on  the  Biliary  Secretion 

3.  Action  on  the  Kidneys 

4.  Action  on  the  Sweat  Glands 

5.  Lachrymal  Glands 
6    Lacteal  Glands    . 

h.  Non- Secretory  Glands     . 


135 


135 
136 
136 

137 
137 
137 
137 
139 

140 
141 
144 
144 
144 
145 
150 
152 
157 
158 
158 
158 


TABLE    OF    CONTENTS, 


Section  V. — Alterations  in  Tissuk  Metabolism 

1.  Energy  of  the  Animal  Oxidizing  Processes 

2.  Deposit  of  Fat  in  the  Body    . 

3.  Diabetes         ......' 

Section    VI. — Alteuations    in     the     REPUODrcTivE 

Functions 

Section  VII. — Alterations  in  Temperature 
Section  VIII. — Action  on  the  Muscles 

1.   Action  on  the  Pupil         .... 
Section  IX  — Action  on  the  Nervous  System 

A.  Action  on  the  Organs  of  Conduction 

B.  Action  on  the  Peripheral  Nerve  Endings 

C.  Action  on  the  Central  Nervous  System  . 

1.  Interference  with  the  Automatic  Functions 

2.  Reflex  and  Co-ordinated  Functions 

3.  Action  on  the  Sensory  Functions 


PAGE 

159 
160 
161 
161 

162 
164 
164 
165 
169 
169 
172 
175 
177 
177 
182 


V. — Investigation  and  Explanation  of  the  Ana- 
tomical Alterations  produced  by  Poisons    .         .185 

VI. — Investigation  of  Chemical  Chan(^:s  produced 
BY  Poisons 188 


APPENDIX. 

1.  Dose,  Immunities,  Form,  and  Solvents  of  Poisons  .  .      189 

2.  Methods  of  Producing  Narcosis      .          .          .          .  .199 
Antagonism  of  Drugs          .          .          .          .          .          .  .194 


Index 19 1 


LIST  OF  ILLUSTRATIONS. 


PIO.  PAGE 

1.  Various  Forms  of  Canult«.     (Brunton)          ...  20 

2.  Diagram  of  a  Frog,  showing   lines  of  different  incis- 

ions.    (Cyon)  ........  34 

.3.  Diagram  of  tlie  Muscles  of  the  Leg  of  a  Frog.    (Cyon)  35 

4.  The  "Nerve-muscle  Preparation."      (Cyon)          .          .  36 

o.   Du  Bois  Reymoud's  Induction  Apparatus.      (Foster)    .  38 

6.  Pohl's  Commutator  or  Double  Key.      (Sanderson)         .  39 

7.  Du  Bois  Reymond's  Key.      (Sanderson)        ...  40 

8.  Arrangement  of  Apparatus  for  Experiments  on  Mus- 

cle and  Nerve.     (Foster)          .....  42 

9.  Muscle  Holder  and  Electrodes.     (Foster)     ...  43 

10.  Plluger's  Myographion.    (Sanderson)   ....  44 

11.  Non-polarizable  Electrode.     (Sanderson)     ...  44 

12.  Marey's  Comparative  Myograph  .....  45 

13.  Czermak's  Rabbit-holder.     (Sanderson)        ,         .         .61 

14.  Bernard's  Dog-holder 62 

15.  Improved  Form  of  Bernard's   Dog-holder   and  Brun- 

ton's  Dog-holder      .         .         .         .         .         .         .62 

16.  Sanderson's  Cardiograph.     (Sanderson)        ...  89 

17.  Marey's  Tympanum  and  Lever.     (Sanderson)      .         .  90 

18.  Ludwig's  Manometer.     (Foster)  .         .         .         .         .93 

19.  Fick's  Spring  Manometer.     (Fost<.'r)    ....  95 

20.  Ludwig's  Kymographion.      (Cyon)        ....  96 

21.  Large  Kymographion,  for  continuous  tracings,    (Foster)  98 

22.  Arterial  Canula 102 

23.  Blood- pressure  Tracing 103 

24.  Hypothetical  Nervous  Apparatus  of  the  Heart.     (Brun- 

ton)            106 

25.  Last  Cervical  and  First  Thoracic  Ganglia  in  the  Rabbit. 

(Foster) 108 


Xll  LIST    OF    ILLUSTRATIONS. 

FIG.  PAilK 

26.  Diajrram  of  the  Ijast  Cervical  and  First  Thoracic  Gan- 

glia in  the  Dog.     (Foster)         .         .         .         .         .109 

27.  Ludwig  and  Coats' s  Frog  Manometer.     (Cyon)    .         .117 

28.  Roy's  Heart  Apparatus 119 

29.  Nervous  Apparatus  of  the  Heart  .         .         .         .123 

30.  Arrangement  of  Apparatus  for  Studying  the  Respiratory 

Movements.     (Foster) 132 

31.  Veins  of  the  Submaxillary  Gland  of  the  Dog.     (Ber- 

nard)         146 

32.  Parts  Exposed  in  Operations  on  the  Submaxillary  Gland 

of  the  Dog.     (Bernard) 147 


INTRODUCTION 


Those  substances  are  called  poisons  which,  when 
introduced  into  the  animal  economy,  produce  disturb- 
ances of  its  normal  functions.  Occasionally  the  term  is 
restricted  to  substances  which  are  active  in  minute  quan- 
tity, and  when  the  disturbance  produced  by  their  action 
threatens  the  life  of  the  organism.  But  since  these 
distinctions  are  merely  relative,  they  are  superfluous, 
especially  since  the  scope  of  toxicology  can  be  defined 
by  other  considerations  than  by  a  definition  of  the  word 
poison ;  the  latter  being  only  important  from  a  medico- 
legal point  of  view. 

Pharmacology  in  its  widest  scope  embraces  the  study  of 
drugs  from  all  possible  points  of  view,  and  the  information 
thereby  acquired  may  be  useful  under  the  most  diverse 
conditions ; — to  the  physician,  to  enable  the  recognition 
and  proper  treatment  of  cases  of  poisoning,  or  to  permit  of 
the  use  of  drugs  for  therapeutic  purposes; — to  the  public, 
to  permit  the  avoidance  of  noxious  substances  ; — to  the 
physiologist  and  pathologist,  to  enable  the  application  of 
information  derived  from  the  study  of  the  action  of  poisons 
to  the  advancement  of  their  sciences.  The  study  of  phar- 
macology can  therefore  be  limited  according  as  one  or 
more  of  these  points  of  view  occupy  the  first  place  in  the 
mind  of  the  investigator.  The  public  desires  to  know  only 
what  substances  are  poisonous,  that  they  may  be  avoided, 
while  their  modus  operandi  is  a  matter  of  indifference. 
Those  poisons  which  are  suitable  for  use  at  the  bedside 
will  prove  most  interesting  to  clinicians. 

Pure  pharmacology  is  best  advanced  by  the  avoidance  of 
2 


14  INTRODUCTION. 

any  special  stand-point,  in  order  that  all  of  its  bearings 
may  be  equally  appreciated,  and  still  more,  since  the 
advancement  of  pure  science  is  always  retarded  by  a 
search  for  that  only  which  promises  immediately  practi- 
cal results.  The  history  of  the  progress  of  the  sciences 
teaches  that  nearly  all  the  most  important  discoveries, 
even  those-  subsequently  of  the  greatest  practical  value, 
resulted  from  investigations  untrammelled  by  a  contin- 
uous mindfulness  of  the  merely  practical.  Thus  phy- 
siology has  rendered  such  inestimable  assistance  to  the 
progress  of  practical  medicine  that  she  can  well  be  re- 
garded as  her  handmaid  ;  but,  nevertheless,  physiology  is 
a  pure  science,  which,  like  physics  and  chemistry,  should 
be  studied  for  its  own  worth,  without  being  hampered  by 
doubts  as  to  whether  its  results  are  immediately  applicable 
to  practical  medicine  or  not.  So  also  pharmacology  is 
growing  more  and  more  worthy  of  occupying  a  similar 
position,  though  it  must  be  acknowledged  that,  as  yet,  it 
is  not  bounded  by  such  sharply  drawn  lines  as  to  consti- 
tute a  distinct  science.  Much,  how^ever,  can  be  gained  in 
this  direction  by  constantly  bearing  in  mind  that  pharma- 
cology has  for  its  object  the  recognition  and  study  of  all 
changes  which  a  foreign  body  can  undergo  or  produce, 
otherwise  than  traumatically,  in  the  organism,  while  the 
questions  as  to  whether  the  substance  under  study  can 
ever  be  Jikely  to  prove  a  poison  to  man,  or  whether  it  has 
properties  which  warrant  its  use  as  a  medicament,  should 
be  kept  in  the  background. 

Consequently  every  substance  which  possesses  ant/ 
active  properties  should  prove  of  interest  to  the  investi- 
gator in  the  domain  of  pharmacology;  while  naturally 
those  substances  will  be  preferred  which  are  either  quite 
unknown,  which  show  results  entirely  novel,  or  whose 
action  admits  of  predetermination  from  a  theoretical 
point  of  view,  as  from  the  stand-point  of  chemical  compo- 
sition. And  it  should,  moreover,  be  remembered,  that 
even  substances  which  themselves  evoke  no  symptoms  in 
the  organism,  may  form  worthy  subjects  of  pharmaco- 
logical investigation  as  throwing  possible  light,  in  the 


TNTRODUCTTON.  15 

changes  which  they  undergo  in  the  s^^stem,  on  the  beha- 
vior of  other  more  active  poisons. 

The  object  of  pharmacology,  therefore,  is  to  acquire 
familiarity  with  the  peculiarities  and  actions  of  poisons, 
to  carefully  analyze  all  processes  which  they  evoke  so  as 
to  obtain  a  complete  picture  of  their  mode  of  action. 
This  object  cannot  be  attained  by  mere  observation  of 
cases  of  poisoning  in  man,  although  such  cases,  when 
properly  studied,  may  be  of  the  greatest  service  ;  since 
it  is  often  only  by  such  means  that  we  are  enabled  to  form 
conclusions  as  to  the  action  of  the  drug  on  man. 

Experiment  must  be  the  instrument  most  relied  on  in 
pharmacology  ;  not  only  because  it  alone  permits  the 
study  of  all  poisons  in  all  doses,  and  on  the  most  various 
organisms  ;  but  because  it  is  indispensable  to  the  acquire- 
ment of  any  more  profound  knowledge  of  the  modus 
operandi  of  poisons  than  can  be  obtained  by  a  mere  in- 
spection of  cases  of  poisoning. 

Observation  of  cases  of  poisoning  only  furnishes  a 
coarse  method  of  observing  the  prominent  features  of  the 
action  of  the  poison,  while  experimentation  alone  ren- 
ders possible  that  analysis  of  the  information  so  acquired 
which  enables  the  deduction  of  an  opinion  as  to  the 
changes  which  the  poison  itself  undergoes,  the  means  by 
which  those  changes  are  produced,  and  their  results  and 
the  special  action  which  they  may  exert  on  individual 
organs.  The  extent  to  which  such  deductions  will  be- 
come possible  will  depend  upon  the  perfection  of  the 
experimental  art  and  the  state  of  our  knowledge  of  the 
normal  functions. 

Experimentation  on  living  animals  is  chiefly  employed 
by  physiologists,  who  are  consequently  pre-eminently 
suited  for  the  study  of  pharmacology.  But  this  is  not 
the  only  explanation  of  the  fact  that  the  authors  of 
most  of  our  most  valuable  papers  on  the  action  of  drugs 
are  practical  physiologists  ;  a  deeper-lying  reason  for  the 
devotion  of  physiologists  to  pharmacology  is  to  be  found 
in  the  fact  that  nearly  every  addition  to  our  knowledge 
of  the  action  of  a  poison  marks  at  the  same  time  an  ad- 


16  INTRODUCTrON. 

vance  in  our  knowledge  of  the  normal  organism,  and  can 
hence  be  regarded  as  a  step  in  the  development  of  the 
science  of  physiology.  Physiologists,  therefore,  rightly 
regard  pharmacological  investigation  as  one  of  the  most 
important  modes  of  advancing  their  science.  Occasion- 
ally, also,  pharmacology  furnishes  an  instrument  of 
experimentation  of  the  most  delicate  character  ;  as  an 
illustration  of  this  we  have  only  to  mention  curare,  whose 
employment  in  pure  physiology  has  been  most  fruitful 
of  valuable  results.^ 

1  [In  this  connection  f^ee  Bernard's  valuable  paper  on  "  Les 
poisons  comme  methode  de  vivisection,"  in  tlie  Revue  Scientifique, 
1875.] 


METHODS 


OF 


PHARMACOLOGICAL  INVESTIGATION. 


The  first  indication  as  to  the  poisonous  action  of  any 
substance  is  usually  to  be  found  in  reports  of  cases  of 
poisoning  occurring  in  man.  But  the  histories  of  such 
cases,  though  they  may  indicate  the  most  promising 
line  of  study,  in  the  majority  of  instances  give  us  only 
an  imperfect,  and  in  the  light  of  experiment,  often  an 
inaccurate  picture  of  the  action  of  the  poison.  The 
consideration  of  suggestions  derived  from  such  sources, 
though  they  may  often  facilitate  the  attainment  of  de- 
finite results,  just  as  a  qualitative  assists  a  quantitative 
chemical  analysis,  will,  however,  for  the  present  be  de- 
ferred. 

When  it  is  desired  to  determine  the  mode  of  action  of 
a  substance  of  whose  modus  operandi  no  conception  has 
been  formed,  one  of  two  lines  of  investigation  may  be 
followed  :  Either  an  animal  is  suitably  brought  under  its 
influence  and  a  general  picture  of  its  working  obtained, 
Avhich,  imperfect  though  it  be,  is  far  better  than  the  gene- 
rality of  reports  of  cases  of  poisoning,  and  which  may 
serve  as  a  starting  point  for  the  explanation,  by  subse- 
quent experiments,  of  individual  symptoms;  or  the  action 
of  the  drug  on  separate,  isolated  organs,  may  first  be 
studied,  and,  assisted  by  this  preparatory  knowledge,  its 
influence  on  the  animal  system  then  determined. 

In  general,  the  first  method  leads  most  directly  to  the 
desired  end.     Nevertheless,  we  will  here  follow  the  latter 

2* 


18  METHODS  OF    INVESTIGATION. 

plan,  since  the  analysis  of  results  obtained  in  the  animal 
organism  presupposes  a  certain  amount  of  experience  in 
explaining  elemental  disturbances  ;  this  the  beginner  can 
best  acquire  by  the  method  first  indicated.  We  will  there- 
fore commence  with  the  methods  for  the  examination  of 
the  action  of  poisons  on  isolated  organs. 


PART  I. 


STUDY  OF  THE  ACTION  OF  A  POISON  ON 
ISOLATED  ORGANS. 


The  organs  of  the  cold-blooded  vertebrates,  especially 
the  frog,  are  best  suited  for  this  method  of  pharmacologi- 
cal investigation,  since,  as  a  rule,  they  are  equally  with 
those  of  mammals  susceptible  to  the  action  of  poisons,  and 
they  may  be  isolated  from  .the  circulation  for  quite  a  while 
without  undergoing  any  essential  alteration.  Not  only 
excised  organs,  such  as  the  heart,  muscles,  nerves,  etc., 
can  be  used  for  this  purpose,  but  the  action  of  the  drug 
can  even  be  restricted  to  certain  portions  of  the  economy 
while  still  in  the  body  ;  since,  on  the  one  hand,  their 
exposure  does  not  necessarily  entail  any  general  dis- 
turbance of  function,  and,  on  the  other,  the  exclusion 
from  the  circulation  of  certain  parts  of  the  body  neither 
destroys  the  functions  of  the  isolated  parts  nor  interferes 
with  the  normal  condition  of  the  remainder.  For  ex- 
ample, the  action  of  the  poison  can  be  limited  to  one 
extremity  ;  or  the  entire  body,  with  the  exception  of  one 
extremity,  can  be  exposed  to  its  influence. 

Until  quite  recently,  the  only  organ  of  warm-blooded 
animals  which  was  capable  of  isolation  for  pharmaco- 
logical studies  was  the  blood,  whose  physiological  status, 
especially  when  kept  at  the  normal  temperature,  is 
readily  maintained  outside  of  the  body. 

[By  improved  methods  of  research  this  line  of  study 
on  mammals  can  now  be  greatly  extended.  The  methods 
will  be  given  in  their  appropriate  chapters.] 


20      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 


Section  I. — Action  on  the  Blood. 

Blood  in  considerable  quantities  can  be  readily  ob- 
tained only  from  warm-blooded  animals,  the  selection  of 
the  animal  depending  on  the  special  point  to  be  studied : 
thus,  when  alterations  in  the  haemoglobin  are  to  be  ex- 
amined, it  is  advisable  to  employ  easily  crystallizing 
blood,  such  as  that  of  the  horse,  dog,  or  guinea-pig. 

[In  order  to  collect  blood,  either  arterial  or  venous, 
uncontaminated  with  foreign  matters,  it  is  necessary  to 
isolate  the  artery  or  vein  and  insert  a  canula  into  the 
vessel.  Various  forms  of  canulae  may  be  employed. 
The  simplest,  and  therefore  the  best,  is  readily  prepared 
by  drawing  out  in  a  lamp  or  gas-flame,  a  piece  of  narrow 
glass  tubing  until  the  desired  diameter  is  attained  ;  when 
by  further  heating  the  points  of  junction  of  the  narrow 
portion  with  the  remainder  of  the  tube,  and  gently  draw- 
ing out  the  tube,  a  constriction  is  made  at  these  points, 
a  and  h  (Fig.  1,  D).     The  narrow  portion  of  the  tube 

Fig.  1. 


A  is  the  ordinary  form  of  metal  canula,  with  a  ring  at  e  by  which  it  can  be 
tied  to  any  larger  tube.  B  is  a  holder  made  of  a  metal  tube  with  a  wooden 
point  to  facilitate  the  introduction  of  A.  1)  represents  the  manner  of  making 
glass  canulse. 

is  then  gently  heated  over  a  small  flame,  drawn  out 
and  then  filed  across  at  c.  The  point  of  the  canula  thus 
made  is  then  to  be  ground  down  obliquely  by  rubbing  on 
a  hone  and  the  edges  rounded  in  the  flame ;  the  large 
end  of  the  canula  is  now  tied  into  a  short  piece  of  rubber 


ACTION    ON    THE    BLOOD.  21 

tubing  and  is  ready  for  use.  In  this  way  a  number  of 
canulae,  which  are  easily  cleaned  and  inserted,  can  be 
made  in  a  few  minutes. 

In  order  to  insert  a  canula  into  a  vessel  the  surface 
must  first  be  freed  from  hair,  and  after  narcotization,  when 
permissible,  the  skin  divided  by  an  incision  about  an  inch 
Ion":  in  the  line  of  the  vessel.  The  connective  tissue  and 
subcutaneous  muscles  over  the  vessel  may  then  be  torn 
away  with  a  pair  of  blunt  hooks,  or  two  pairs  of  forceps, 
and  the  vessel  carefully  and  thoroughly  freed  from  its  con- 
nective tissue  sheath  ;  on  the  success  of  this  step,  particu- 
larly in  the  case  of  veins,  will  depend  the  readiness  with 
which  the  canula  can  be  inserted,  since  after  the  vein  has 
been  opened  it  will  immediately  collapse  and  it  will  then 
be  found  much  easier  to  insert  the  canula  into  the  space 
between  the  sheath  and  vessel  than  into  its  proper  place. 
Ordinarily,  except  in  the  case  of  large  animals  with  strong 
connective  tissue  fibres,  this  method  of  exposing  the  vessel 
is  preferable,  in  the  avoidance  of  hemorrhage,  to  the  use 
of  any  cutting  instrument;  when,  however,  knife  or  scis- 
sors must  be  employed,  the  bleeding,  if  any  is  caused, 
must  be  controlled  by  ligatures  or  torsion.  After  the 
vessel  has  been  exposed,  a  pair  of  forceps  can  be  passed 
under  it  and  then  opened,  thus  serving  to  maintain  the 
vessel  in  a  position  where  it  can  be  readily  operated  on. 
Three  ligatures  are  then  passed  under  the  vessel ;  if  it 
is  an  artery,  the  one  farthest  removed  from  the  heart  is 
first  tightly  tied,  so  as  to  occlude  the  vessel,  and  the  one 
nearest  the  heart  is  then  tied  in  a  slip-knot  so  as  to  be 
readily  removed.  A  snip  is  then  made  in  the  vessel 
midway  between  the  two  ligatures  with  a  pair  of  scissors 
which  cut  well  at  their  points,  and  the  canula,  which  may 
conveniently  be  held  on  a  piece  of  wood,  then  inserted 
towards  the  heart  and  bound  fast  by  the  middle  thread, 
the  knot  being  tied  around  the  neck  of  the  canula.  The 
canula  is  further  prevented  from  slipping  out  by  bring- 
ing the  ends  of  the  middle  ligature  parallel  with  the  tube 
and  then  encircling  them  with  a  thread  tied  around  the 
large  end  of  the  tube,  and  tying  the  ends  of  both  sets 


22      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

together.  The  same  manipulations  are  used  when  it  is 
desired  to  insert  a  canula  into  a  vein,  with  the  exception 
that  the  proximal  lii^ature  is  first  tied  so  as  to  distend 
the  vessel,  and  the  slip- knot  then  tied  with  the  distal  liga- 
ture, the  canula  pointing  towards  the  periphery  instead 
of  towards  the  heart,  as  in  the  case  of  the  artery.  In- 
stead of  slip-knots,  spring-clips  may  be  used  to  compress 
the  vessels.  Blood  is  then  collected  by  connecting  the 
canula  with  a  clean  glass  tube  leading  to  a  well-cleaned 
vessel  of  any  sort,  preferably  glass,  and  then  untying 
the  slip-knot,  or  removing  the  bull-dog  forceps  or  clip. 

In  order  to  collect  blood  free  from  access  of  air,  the 
canula  may  be  connected  by  tubing  with  the  upper  end 
of  a  burette,  protected  by  a  stopcock,  the  lower  end  of 
which  communicates,  a  stopcock  intervening,  with  a 
movable  vessel  containing  mercury.  The  mercury  reser- 
voir is  first  to  be  raised  to  such  a  height  that  the  mercury 
rises  to  the  top  of  the  burette  and  commences  to  flow 
over  ;  the  lower  stopcock  is  then  closed  and  the  reservoir 
depressed  ;  the  clip  or  knot  is  then  removed  from  the 
vessel  and  the  instant  the  blood  reaches  the  end  of  the 
tubing  connected  with  the  canula,  all  air  being  expelled, 
the  end  of  the  tube  is  slipped  over  the  top  of  the  burette 
and  bound  fast.  On  now  opening  the  lower  stopcock 
of  the  burette  the  mercury  falls  and  draws  after  it  into 
the  burette  the  blood  from  the  vessel.  As  soon  as 
enough  is  obtained,  the  stopcocks  are  closed,  and  the 
tube  may  be  shaken  to  defibrinate  its  contents.] 

In  addition  to  the  action  of  the  drug  on  blood  removed 
from  the  body,  it  is  often  advisable  to  examine  the  blood 
while  still  circulating  in  the  vessels,  as  can  be  readily 
done  in  the  tongue,  or  swimming  bladder  of  frogs,  or  in 
the  mesentery  of  mammals,  with  the  aid  of  the  microscope ; 
in  such  experiments  the  poison  is  injected  into  the  general 
circulation. 

As  far  as  pharmacological  studies  have  yet  taught,  we 
may  have  to  deal  with  the  following  forms  of  alteration  of 
the  blood  produced  by  poisons.  We  commence  with  those 
most  readily  detected. 


action  on  the  blood.  23 

1.  Alterations  in  Consistence,  from  Action  on 
THE  Albuminoids  of  the  Blood. — Caustic  alkalies  can 
convert  the  blood  into  a  gelatinous  mass  by  the  produc- 
tion of  alkali-albuminate.  By  prolonged  action,  alcohol 
coagulates  the  albuminoids  of  the  blood ;  many  metals,  al- 
cohol by  short  action,  aniline,  etc.,  precipitate  them. 
Precipitation  of  globulin  is  produced  by  acids,  and  when 
in  concentrated  solutions,  other  albuminoids  also  are 
thrown  down.  Alterations  in  color  ordinarily  accompany 
changes  in  consistency ;  these  will  be  subsequently 
studied. 

As  a  rule  it  will  not  be  possible  to  determine  the 
character  of  the  precipitate  ;  at  least  when  some  general 
idea  of  the  action  of  the  substance  experimented  with  is 
not  already  possessed,  no  general  rule  for  its  closer  study 
can  be  given,  since  so  little  precise  knowledge  is  pos- 
sessed of  the  alterations  of  the  albuminoids,  that  each  case 
requires  a  special  chemical  study.  It  may  be  recom- 
mended, however,  in  order  to  obtain  some  conception  of 
the  nature  of  the  albuminoid  to  whose  alteration  the 
changes  are  due,  not  only  to  experiment  with  blood 
collected  directly  from  the  artery  or  vein,  but  also  to 
examine  into  the  action  of  the  poison  on  defibrinated 
blood  and  on  blood  serum. 

2.  Alterations  in  the  Alkaline  Reaction  of  the 
Blood. — The  reaction  of  the  blood  cannot  be  directly 
tested  with  litmus  paper.  One  of  the  simplest  methods 
is  tliat  recommended  by  Kiihne.^  It  consists  in  placing 
the  blood  in  a  small  dialyzer,  made  by  moulding  a  piece 
of  parchment  paper  into  the  form  of  a  minute  cup,  and 
floating  the  dialyzer  on  the  surface  of  a  little  distilled 
water  in  a  watch  glass.  A  little  blood  is  then  placed  in 
the  dialyzer  thus  constructed  and  after  a  short  interval 
the  reaction  of  the  colorless  drop  of  water  in  the  watch- 
glass  is  tested. 

[This  method  is,  however,  not  perfectly  reliable,  since 

'  Archiv  f.  Path.  Anat.,  xxxiii.  95. 


24      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

the  blood  will  probably  coagulate  before  the  reaction 
can  be  determined,  and  the  alkalinity  may  possibly  be 
thereby  altered  ;  but,  though  not  giving,  strictly  speak- 
ing, the  reaction  of  fresh  blood,  it  will  generally  serve 
the  purpose. 

Liebreich  recommends  the  use  of  a  slab  of  neutral 
plaster  of  Paris  stained  with  neutral  litmus  solution  ;  a 
few  drops  of  blood  are  allowed  to  fall  on  the  slab,  and, 
after  a  few  seconds  washed  oif  with  a  little  water:  the 
blue  coloration  can  then  be  detected  where  the  blood 
rested.  In  order  to  determine  the  degree  of  alkalinity, 
a  standard  solution  of  tartaric  acid  may  be  made  by  dis- 
solving 7.5  grm.  of  crystallized  tartaric  acid  in  a  litre  of 
distilled  water ;  1  c.  c.  of  this  solution  should  exactly 
neutralize  0.004  grm.  of  sodium  hydrate.  The  acid 
solution  is  added  from  a  burette  to  50  or  100  c.  c.  of  the 
serum  or  blood,  a  drop  of  the  mixture  being  placed  from 
time  to  time  upon  the  slab  colored  with  litmus  ;  the  ad- 
dition of  acid  is  continued  until  the  reaction  is  faintly 
acid.  The  alkalinity  of  the  blood  may  then  be  expressed 
as  corresponding  to  x  milligrammes  of  sodium  hydrate 
per  100  c.  c.  of  blood.]i 

An  even  shorter  method  [based  on  the  fact  that  blood 
coloring  matter  does  not  diffuse  out  of  the  blood  cor- 
puscles into  strong  solutions  of  common  salt]  is  that 
advised  by  Zuntz.^  A  drop  of  blood  is  placed  on  a  strip 
of  glazed  litmus  paper  which  has .  been  previously  moist- 
ened with  a  concentrated  solution  of  sodium  chloride,  and, 
after  a  few  minutes'  contact,  drawn  up  with  a  pipette  or 
filter  paper.  It  is  only  necessary  to  be  sure  that  the 
salt  solution,  which  itself  often  becomes  alkaline  when 
kept  for  any  length  of  time  in  glass  vessels,  is  neutral. 
By  this  process  it  is  also  possible  to  determine  the 
degree  of  alkalinity  of  the  blood  by  adding  standard 
solutions  of  acid  to  the  blood  and  employing  this  method 
to  determine  when  the  reaction  is  acid.     [It  may,  how- 

'  Gamgee,  Physiological  Chemistry,  vol.  i.  p.  177. 
2  Centralb.  f.  d.  Med.  Wissen.,  1867,  531. 


ACTION    ON    THE    BLOOD.  25 

ever,  be  objected  to  this  method,  that  the  addition  of  the 
salt  causes  alterations  in  the  corpuscles,  producing 
shrinkage  and  osmoses  into  the  blood  plasma.  Schafer^ 
recommends  the  use  of  the  delicately  colored  glazed 
English  litmus  paper ;  all  that  is  necessary,  according 
to  him,  is  to  place  a  drop  of  blood  on  the  paper  and  after 
a  few  seconds  to  wipe  it  off.  The  blue  patch  will  indi- 
cate the  alkalinity,  since  the  alkaline  salts  will  soak  into 
this  paper  faster  then  will  the  haemoglobin.] 

3.  Alterations  in  the  Red  Blood-Corpuscles. — For 
studies  on  this  point,  when  the  poison  is  a  liquid  and 
not  volatile,  a  few  drops  of  perfectly  fresh,  defibrinated 
blood  are  placed  on  an  object-glass,  covered  with  a  cover- 
slip,  and  a  drop  of  the  poison  placed  on  the  slide  and 
allowed  to  mingle  with  the  blood  under  the  cover-slip. 
If  it  is  not  desired  to  study  all  the  steps  in  the  process 
of  change,  if  any  should  be  produced  by  the  drug  in 
question,  the  poison  and  the  blood  may  be  first  mixed 
and  a  drop  of  the  mixture  then  placed  upon  a  slide  and 
examined  under  the  microscope.  If,  however,  the  drug 
is  in  the  form  of  a  solution,  great  care  must  be  observed 
in  attributing  the  results  to  the  action  of  the  drug,  as 
there  is  scarcely  any 'known  solvent  which  does  not  itself 
produce  change  in  the  red  blood-corpuscles ;  in  such 
cases  control  experiments  must  be  made  with  the  solvent 
alone.  In  suitable  cases,  0.5-0.7  per  cent,  solution  of 
sodium  chloride,  which  itself  produces  no  sensible  action 
on  the  corpuscles,  m^y  be  used  as  a  solvent.  If  the 
drug  is  a  volatile  liquid,  the  blood  may  be  subjected  to 
the  action  of  its  vapor  by  passing  air  or  any  indifferent 
gas  through  the  liquid  and  then  through  the  blood,  in 
the  manner  to  be  described  under  the  study  of  the  action 
of  gases  [or  any  of  the  gas-chambers,  e.  ^.,  Strieker's  may 
be  used]. 

The  simplest  method  of  subjecting  blood  to  the  action 
of  gases  or  vapors,  is  to  pass  them  through  a  tube  reaching 

'  Journal  of  Physiology,  Jan.  1882. 


28      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

to  the  bottom  of  the  vessel  in  which  the  blood  is  contained. 
The  process  may  be  accelerated  by  closing  the  vessel 
which  contains  the  blood  after  the  air  has  been  displaced 
by  the  gas,  and  then  agitating.  If  it  is  desired,  during 
the  action  of  the  gas,  entirely  to  prevent  the  access  of 
air,  a  small  quantity  of  blood  may  be  passed  up  into  an 
ordinary  Torricellian  barometer  tube,  and  then  the  gas 
conducted  through  it ;  the  action  of  the  gas  may  then  be 
facilitated  by  closing  the  open  end  of  the  tube  with  the 
finger  and  then  shaking,  though  it  should  be  remembered 
that  shaking  blood  w^ith  finely  divided  solid  particles,  and 
therefore  probably  also  with  the  globules  of  mercury, 
may  itself  cause  an  alteration  in  the  blood  corpuscles.' 

The  continuous  passage  of  gases  through  undiluted 
blood,  as  is  here  desirable,  is,  by  any  of  the  methods  yet 
mentioned,  an  extremely  unsatisfactory  and  incomplete 
procedure  on  account  of  the  foam  produced  ;  since  each 
gas  bubble  only  comes  into  partial  contact  with  a  limited 
portion  of  the  blood,  and  the  complete  result  of  the  treat- 
ment may  only  appear  after  a  long  interval  of  time.  By 
the  following  method,^  however,  the  object  is  rapidly 
attained  ;  a  vertical  glass  tube,  about  5  mm.  in  diameter, 
and  on  which  there  may  with  advantage  be  blown  a 
number  of  bulbs,  is  to  be  bent  at  its  lower  end  so  as  to 
form  a  short  arm  formino;  an  acute  anHe  with  the  verti- 
cal  portion  of  the  tube.  A  small  portion  of  blood  is  now 
drawn  by  suction  into  the  tube  so  as  to  occupy  a  part  of 
both  of  its  arms  and  the  shorter  arm  is  then  connected 
with  the  gas  generator.  The  gas  then  forces  the  blood 
up  into  the  vertical  arm,  bursts  through  it  in  bubbles, 
and  the  blood  flows  back  along  the  sides  of  the  tube  to 
be  again  forced  up  by  the  gas,  thus  always  bringing  fresh 
surfaces  into  contact  with  the  gas,  and  producing  a  com- 
plete action  in  the  shortest  possible  time. 

In  certain  special  cases,  it  may  be  desirable  to  keep 

1  Compare  A.  Rollet,  Sitzungsber.  d.  Wiener  Acad.  Math.  Natur. 
Wissen.  CI.  2  Abth.  lii.  246. 

■^  Hermann,  Arch.  f.  Anal.  u.  Phys.  1865,  471. 


ACTIOxV    ON    THE    BLOOD.  27 

the  blood,  which  has  been  subjected  to  the  action  of  the 
gas,  free  from  access  of  air ;  it  is  then  only  necessary  to 
seal  the  tube,  after  introducing  the  blood  and  gas,  by 
fusion  at  two  points  where  it  has  previously  been  drawn 
out  to  a  thread.  If  it  is  necessary  to  observe  the  action 
of  the  gas  at  a  high  or  low  temperature,  the  tube  may 
be  bent  in  the  form  of  a  V?  ^^^  during  the  experiment 
immersed  in  a  water-bath  or  cooling-mixture. 

The  methods  as  yet  described  do  not  permit  of  continu- 
ous observation  from  the  commencement  of  the  action  of 
the  gas  on  the  blood-corpuscles  ;  this,  however,  is  ren- 
dered possible  by  the  use  of  the  dift'erent  forms  of  gas- 
chambers  for  microscopic  use,  most  of  which  also  permit 
of  the  object  being  studied  at  different  temperatures.^ 

The  alterations  of  the  red  blood-corpuscles  produced  by 
different  agents,^  as  far  as  are  yet  known,  may  be  changes 
in  shape  or  color,  or  complete  decolorization  or  solution. 
The  latter  two  processes,  of  which  the  first  may,  for  ex- 
ample, be  produced  by  water,  and  the  second  by  ether, 
cause  the  blood  to  assume  the  appearance  known  as 
"  lak^^"  While  normal  blood,  even  in  the  thinnest 
layers,  is  perfectly  opaque,  and  when  allowed  to  flow" 
down  the  side  of  a  orlass  forms  irre«!;ular  streaks,  after 
decolorization,  or  solution  of  the  red  corpuscles,  it  be- 
comes transparent  and  perfectly  homogeneous,  like  red 
varnish.  Under  tlie  microscope,  in  both  cases,  the  serum 
is  seen  to  be  colored,  and  the  corpuscles  are  either  entirely 
invisible,  or  in  simple  decolorization,  occur  in  the  form  of 
perfectly  pale,  scarcely  perceptible  spheres.  ["  Stro- 
mata"  according  to  Rollet.] 

The  change  of  the  disk-shape  into  the  spherical  form 
seems  always  to  precede  the  loss  of  color,  even  when 
the  latter  is  caused  by  the  total  solution  of  the  corpus- 
cle. In  addition  to  this  spherical  alteration  in  the 
shape  of  the  red  blood-corpuscles,  they  may  also  take  on 

'  Kiihue,  Arch.  f.  Path.  Aiiat.  xxxiv.  423,  and  Strieker's  Hand- 
biicli,  p.  411. 

2  The  alterations  produced  by  heat,  cold,  electricity,  etc.,  do  not 
fall  within  the  province  of  this  work. 


28       ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

a  jagged,  contracted  form  (crenated)  from  the  action  of 
certain  reagents,  for  example,  as  occurs  on  the  addition 
of  concentrated  salt  solution  or  on  drying. 

Alterations  in  color  of  the  corpuscles  will  be  mentioned 
under  the  heading  of  changes  in  the  coloring  matter  of 
the  blood. 

4.  Alterations  in  the  White  Corpuscles. — The 
white  blood-corpuscles  may  be  studied  in  precisely  the 
same  manner  as  the  red.  In  the  former  case,  however,  it 
is  necessary  in  addition  to  examine  into  the  eft'ect  of  the 
agent  on  the  contractility  of  the  white  corpuscles  :  this 
may  be  accomplished  by  experimenting  with  a  drop  of 
blood  on  the  warm  stage  of  the  microscope. 


— In  order  to  form  any  conclusion  as  to  this  point,  it  is 
evidently  necessary  to  subject  the  blood  to  the  action  of 
the  poison  the  instant  that  it  leaves  the  bloodvessels.  Co- 
agulation may  be  either  accelerated,  retarded,  or  pre- 
vented. 

Should  the  blood,  after  the  addition  of  the  poison, 
appear  to  coagulate  more  rapidly  than  normal,  a  control 
experiment  must  be  made  by  adding  some  of  the  poison 
to  defibrinated  blood  in  order  to  determine  whether  the 
coagulation  is  due  to  fibrin-formation  or  to  the  coagu- 
lation of  albuminoids,  etc.  [The  coagulum  formed,  and 
the  process  of  its  formation,  may  also  advantageously  be 
examined  under  the  microscope.] 

According  to  the  researches  of  Alexander  Schmidt,^ 
retardation  or  prevention  of  coagulation  depends  upon 
action  of  the  poison  either  on  the  fibrinogen  or  the  fibrino- 
plastin. 

When,  therefore,  coagulation  is  retarded,  the  mode 
of  action  may  be  determined  by  allowing  the  drug  to  act 
either  on  isolated  fibrinogen  or  fibrinoplastic  substance,  and 
then  determining  their  individual  activities.     Fibrinogen 

»  Arch.  f.  Aiiat.  ii.  Pliys.  1B61,  p.  545,  675  ;  1862,  428,  533. 


AcrroN  ON  THE  blood.  29 

can  be  readily  obtained  in  the  pericardial  fluids  of  man 
or  other  mammals,  and  in  most  hydrocele  fluids  ;  its  pres- 
ence, however,  in  these  liquids  must  be  first  established 
by  the  production  of  a  coagulum  when  they  are  added  to 
the  serum  obtained  by  subjecting  blood-clots  to  pressure. 
Fibrino plastic  substance  may  be  obtained  from  the  fluid 
thus  obtained  from  blood  coagula.  Fuller  details  for  in- 
vestigations on  these  points  must  be  obtained  from 
Schmidt's  memoir. 

[The  comparatively  recent  researches  of  Hamraarsten^ 
on  the  chemistry  of  blood  coagulation  have  rendered 
necessary  some  modification  of  the  theories  of  Schmidt 
and  Buchanan.  According  to  his  investigations  the  evi- 
dence is  decidly  in  favor  of  the  view  that  fibrin  is  pro- 
duced by  the  decomposition  or  change  of  fibrinogen,  and 
that  this  change  is  connected  with  the  presence  of  a 
ferment  derived  from  the  breaking  down  of  the  white 
corpuscles,  or,  perhaps,  from  the  granular  bodies  recently 
described  by  Bizzozero.  Paraglobulin,  or  the  fibrino- 
plastic  substance,  is  therefore  only  indirectly,  if  at  all, 
connected  with  the  process ;  at  any  rate  the  idea  that 
fibrin  can  only  be  formed  by  the  union  of  fibrinogen  and 
fibrinoplastin  in  the  presence  of  a  ferment  is  no  longer 
tenable. 

The  same  methods,  however,  can  be  employed  as  indi- 
cated above,  since  the  ferment  is  contained  in  the  serum 
expressed  from  blood  clots.] 

6.  Alterations  in  the  Coloring  Matter  of  the 
Blood. — For  studies  on  this  point  it  is  advisable  to  dilute 
the  blood  which  has  been  treated  wMth  the  poison,  with 
water,  so  as  to  be  able  to  study  changes  in  its  color  w^ith 
transmitted  light ;  generally  the  dilution  should  precede 
the  addition  of  the  poison. 

Changes  in  haemaglobin  are  best  and  easiest  studied 
by  means  of  the  spectroscope,  as  described  in   Hoppe- 

'  Pfliiger's  Archiv,  xiv.  xvii.  xviii.  xix. 
3* 


30      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

Seyler's  Chemische  Analyse.  [See  also  the  paper  by 
Gamgee  on  the  action  of  "  Nitrites  on  the  Blood,"  Proc. 
of  the  Roy.  Soc,  1868,  p.  339.] 

7.  Alterations  in  the  Gases  of  the  Blood  and 
IN  THE  Power  of  Absorbing  Gases. — From  the  fact 
that  when  blood  is  drawn  from  a  vessel  changes  in  the 
proportion  of  its  contained  gases  at  once  commence,  the 
action  of  a  drug  on  the  blood  gases  can  be  only  partially 
determined. 

For  example,  if  oxygen  is  diminished  in  proportion,  or 
entirely  absent,  it  would  be  made  evident  by  the  change 
of  color  to  a  dark  venous  hue  and  by  the  characteristic 
spectroscopic  changes  ;  changes  in  percentage  of  carbonic 
anhydride  are  however  much  more  difficult  to  establish. 

iVccurate  experiments  on  either  of  these  questions  are 
extremely  difficult ;  the  blood  must  be  collected  without 
access  of  air  and  then  subjected  to  the  action  of  the 
poison  and  the  gases  then  determined  ;  or  its  power  of 
absorption  for  certain  gases  established  after  the  blood, 
from  which  all  gases  have  been  exhausted,  has  been 
brought  under  the  influence  of  the  poison.  Both  these 
processes  are  complicated  and  will  be  rarely  requisite 
in  pharmacological  studies  ;  they  Avill  therefore  not  be 
entered  into  here. 

8.  Alterations  in  the  Ozone  and  Ozonizing  Power 
OF  THE  Blood. — For  the  determination  of  the  first  of 
these  points,  the  blood  must  be  preserved  throughout 
free  from  air,  since  ozone  is  formed  as  soon  as  blood 
comes  in  contact  with  the  atmosphere.  The  blood  must 
therefore  be  collected  in  a  vacuum,  or  in  an  atmosphere 
free  from  oxygen,  then  mixed  with  the  poison,  and  the 
surrounding  air,  which  is  then  allowed  access,  tested  with 
freshly  prepared  guaiacum  test-paper  (or  strips  of  paper 
moistened  with  a  solution  of  iodide  of  potassium  and 
starch ;  if  ozone  is  formed  it  will  unite  with  the  potassium, 
the  iodine  will  be  set  free  and  color  the  starch  blue). 


ACTION    ON    THE    MUSCLE3.  31 

Full  details  for  such  studies  will  be  found  in  Kiihne 
and  Scholz  on  "  Ozone  in  the  Blood. "^ 

In  order  to  determine  the  ozonizing  power  of  the 
blood,  it  must  be  treated  with  carbon  monoxide  gas,  ex- 
hausted of  oxygen,  and  then  brought  under  the  action 
of  the  poison;  the  presence  or  absence  of  ozone  in  the 
air  can  then  be  determined  by  test  papers.  In  order  to 
determine  the  readiness  with  which  the  blood  yields  up 
its  ozone  (?)  a  more  delicate  test  than  guaiac  must  be 
employed  ;  the  best  process  is  to  add  a  small  quantity  of 
tincture  of  guaiacum  to  a  drop  of  oil  of  turpentine  and 
then  a  few  drops  of  the  blood  Avhich  has  been  acted  on 
by  the  poison.  If  the  power  of  transferrence  is  unaltered, 
the  fluid  will  immediately  become  dark  blue. 

For  the  study  of  other  alterations  of  the  blood,  such 
as  precipitation,  or  alterations  in  the  poison  produced 
by  the  action  of  the  blood,  no  general  rules  can  be  given. 


Section  II. — Action  on  the  Muscles. 

Only  a  few  poisons  are  suitable  for  direct  application 
to  excised  muscles ;  of  course  in  these  cases,  the  muscles 
of  cold-blooded  animals  alone  can  be  used,  those  of  the 
frog  being  nearly  always  selected. 

Since  most  poisons  must  be  used  in  the  form  of  a  solu- 
tion, and  since  nearly  all  solvents,  even  distilled  water, 
are  irritating  to  muscles,  the  direct  immersion  of  a  mus- 
cle in  a  solution  of  a  poison  is  always  a  doubtful  experi- 
ment. A  solution  of  common  salt,  0.5-0.7  per  cent.,  is 
the  most  neutral  solvent  that  can  be  selected. ^ 

A  better  method  than  the  immersion  of  the  muscle 
in  the  solution,  is  to  determine  the  local  action  of  the 
poison  by  injecting  the  solution  into  the  bloodvessels  ; 
[this  can  be  readily  accomplished  in  the  frog  by  insert- 
ing a  canula  in  the  bulbus  aortcie,  washing  out  the  circu- 

^  Arcli.  f.  Path.  Anat.,  xxiii.  p.  96. 

2  Sf^e  Nasse,  Arch.  f.  d.  ges.  Physiol,  ii.  97. 


32      ACTION    OF    POTSONS    ON    ISOLATED    ORGANS. 

lation  with  salt  solution,  and  then  making  an  injection 
of  the  poison.  By  this  means  the  effects  of  local  action 
on  the  muscles  can  be  readily  studied.] 

Gases  and  vapors  are  best  suited  for  direct  applica- 
tion to  the  muscles  ;  to  accomplish  this,  the  muscle  is  sus- 
pended in  a  bottle,  or  cylindrical  vessel,  closed  by  a  cork 
through  which  pass  two  tubes  ;  one  simply  traversing  the 
cork,  the  other,  through  which  the  gas  is  to  be  conducted, 
passing  to  the  bottom  of  the  vessel  and  dipping  under 
the  surface  of  a  layer  of  water.  When  the  gas  is  forced 
through  the  vessel  it  comes  in  direct  contact  with  the 
muscle  and,  at  the  same  time,  keeps  the  atmosphere 
around  the  muscle  saturated  with  aqueous  vapor,  a  con- 
dition absolutely  necessary  for  all  experiments  on  muscles 
or  nerves. 

It  is  convenient  to  so  suspend  the  muscle,  that  it  can 
be  readily  irritated  while  still  within  the  vessel.  A  fine 
wire,  passing  through  the  cork  and  ending  in  a  hook  on 
which  the  tendon  or  bone  is  suspended,  can  serve  as  one 
electrode  ;  a  very  light  metal  hook,  connected  with  a 
fine  spiral  wire  which  also  passes  through  the  cork, 
can  be  inserted  in  the  other  tendon  and  serve  for  the 
second  electrode.  For  experiments  with  gases  and 
vapors  the  thinnest  possible  muscles,  such  as  the  sartorius 
of  the  fro,£:,  must  be  selected,  since  the  gases  act  solely 
on  the  superficial  fibres. 

For  the  majority  of  poisons  it  is  best  to  first  adminis- 
ter the  drug,  in  a  way  which  will  be  later  indicated,  to 
uninjured  animals,  and  then,  after  the  action  of  the 
poison  has  become  evident,  to  excise  their  muscles  for 
investigation.  It  is  very  often  desirable,  as  a  control 
experiment,  to  study  at  the  same  time  an  unpoisoned 
muscle  of  the  same  animal.  In  the  frog,  which  is  alone 
suitable  for  such  experiments,  single  groups  of  muscles 
may  readily  be  protected  from  the  poison  by  ligation  of 
their  arteries  before  the  drug  is  administered.  This  is 
most  easily  accomplished  by  shutting  off  the  blood  supply 
from  one  entire  limb  by  ligation  of  the  common  iliac 
artery,  or   the    femoral    artery  may  be    ligated  at  the 


ACTION    ON    THE    MUSCLES.  33 

upper  part  of  the  thigh  and  the  foot  and  leg  of  that  side 
be  thus  cut  oft'  from  tlie  circulation. 

[Ligation  of  the  bloodvessels  of  a  limb  will  not  inva- 
riably succeed  in  preventing  access  of  the  poison  to  that 
member,  since  Ringer  and  MurrelP  have  found  that  cer- 
tain substances,  such  as  potash  salts,  are  capable  of  be- 
ing diffused  through  tissues  shut  off  from  the  circulation 
almost  as  rapidly  and  as  thoroughly  as  when  their  blood 
supply  has  not  been  interfered  with.  In  cases,  therefore, 
where  ligation  of  the  blood  supply  of  a  limb  appears  to 
produce  no  modification  in  the  character  of  the  symptoms, 
which  on  other  grounds  are  presumably  of  peripheral 
origin,  the  tissues  should  always  be  examined  for  the 
presence  of  the  poison.] 

The  ligation  of  a  common  iliac  artery  is  performed  in 
the  foUowins;  manner :  The  froor  beiuiz;  fastened  on  his 
belly,  in  the  lower  part  of  the  back  three  bony  lines  are 
easily  detected,  the  two  iliac  bones  and  between  them 
the  coccyx  ;  an  incision  is  to  be  made,  parallel  to  these 
bones,  between  the  ilium  and  coccyx,  through  the  oblique 
muscular  mass,  the  ileo-coccygeus  ;  the  iliac  plexus  can 
then  be  seen,  composed  of  the  prominent  nerve  trunks, 
lying  deep  within  the  peritoneal  cavity,  and  at  its  inner 
border,  the  common  iliac  artery.  The  artery  can  then 
be  readily  isolated  with  a  delicate  blunt  hook,  and  a  fine 
thread  passed  around  it  and  ligated. 

To  ligate  the  femoral  artery,  a  frog  is  fastened  in  the 
same  manner  and  a  longitudinal  incision,  m,  n  (Fig.  2.), 
made  through  the  skin  in  about  the  middle  of  the  posterior 
surface  of  the  thigh;  a  deep  longitudinal  furrow  is  then 
seen  lying  between  the  vastus  externus  on  the  outer  side 
and  the  semimembranosus  on  the  inner  side,  with  the  thin 
round  biceps  lying  in  the  furrow  (Fig.  3) ;  on  drawing 
the  vastus  with  the  biceps  towards  the  outer  side  and  cut- 
ting through  the  fascia,  the  sciatic  nerve  and  femoral 
artery  are  seen  running  together,  the  latter  being  easily 
recognized  by  its  black  pigmentation  ;  it  is  to  be  sepa- 

^  Joiirii.  of  Phys.,  vol.  i.  pt.  i. 


34      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

rated  from  the  nerve  with  a  blunt  hook  and  ligated.     If 
it  is  desired  to  ligate  the  artery  near  the  knee-joint,  the 


Fi-.  2. 


JJiagram  of  a  fi'oj(  to  show  the  lines  of  various  iucisious. 

biceps  is  first  to  be  divided  at  its  lower  end  and  turned 
upwards ;  the  artery  can  then  be  readily  reached. 

The  method  of  preparation  of  the  muscle  for  study 
after  poisoning,  will  depend  upon  the  special  point  to 
be  investigated.  For  the  examination  of  the  relative 
irritability,  etc.,  it  is  always  advisable  to  isolate  the 
muscle  with  as  long  a  piece  of  its  nerve  as  possible  ;  for 
most  purposes,  especially  when  it  is  desired  to  load  the 
suspended  muscle,  the  gastrocnemius  in  connection  with 


ACTION    ON    THE    MUSCLES. 


35 


the  sciatic  nerve  and  femur  is  the  most  suitable  prepara- 
tion. Ordinarily,  however,  the  condition  of  irritability 
is  alone  dealt  with,  and  for  the  examination  of  this  point 
the  method  of  Du  Bois  Reymond  is  perhaps  the  simplest. 
His  preparation  is  made  as  follows  :   After  destruction  of 


Diagram  of  the  muscles  of  the  leg  of  a  frog,  posterior  surface,  a,  triceps 
femoris  ;  ft,  biceps  femoris  ;  c,  semimembranosus  ;  d,  coccygeo-iliacus  ;  e,  /, 
tendo  Achillis  ;  g,  gastrocnemius  ;  h,  head  of  gastrocnemius  ;  k,  peroneus,  the 
outer  muscle  marked  k  is  the  tibialis  anticus  ;  I,  rectus  internus  ;  n,  pyriforniis  ; 
.r,  coccyx  ;  y,  ilium  ;  a',  vastus  externus. 

the  central  nervous  system,  by  thrusting  a  wire  down 
the  spinal  canal  and  into  the  cerebral  cavity,  the  frog  is 
cut  in  two  in  the  lower  dorsal  region  with  a  pair  of  strong 
scissors,  and  the  skin  stripped  off  the  lower  extremities  ; 
the  furrow  between  the  vastus  externus  and  semimem- 
branosus is  then  sought  for,  and  the  sciatic  nerve  isolated 
as  near  the  knee  as  possible.  A  blade  of  a  sharp  pair 
of  scissors  is  then  carefully  passed  under  the  nerve  and 
the  leg  amputated  near  the  knee,  care  being  taken  not 
to  injure  the  nerve.  The  foot  is  then  held  between  the 
fingers,  and  the  nerve  carefully  dissected  out  from  below 
upwards  to  the  spinal  column,  and  all  branches  divided. 


36       ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 


Fig.  4. 


great  care  beino;  taken  not  to  stretch  the  nerve  or  injure  it 
with  the  scissors.  The  most  difficult  part  to  isolate 
safely  is  where  the  nerve  enters  the 
abdominal  cavity.  \¥hen  the  spinal 
column  is  reached,  the  plexus  which 
forms  the  sciatic  is  to  be  divided.  [The 
preparation  generally  known  as  the 
"  nerve-muscle  preparation"  is  obtained 
by  a  slight  modification  of  this  method. 
The  femur  is  divided  about  half  an  inch 
above  the  knee  and  the  nerve  prepared 
as  above  ;  the  gastrocnemius  muscle  is 
then  exposed,  its  tendon  divided  as  near 
the  foot  as  possible,  and  the  muscle  sepa- 
rated by  a  blunt  probe  from  the  rest  of 
the  leg  which  is  then  divided  helow  the 
knee.  The  preparation  then  consists 
of  the  entire  sciatic  nerve  from  the 
knee  up  to  the  vertebral  column,  the 
knee-joint  with  a  portion  of  femur  by 
which  it  can  be  suspended,  and  the  gas- 
trocmius  muscle  (Fig  4).] 

All  preparations  of  frogs'  nerves  and 
muscles  must  be  carefully  protected 
from  drying. 

1.  Measurements  of  the  electro-motive  power  of  poi- 
soned muscles  will  be  seldom  required,  since  there  seems 
to  be  ground  for  believing  that  the  electro-motive  power 
runs  parallel  Avith  its  irritability.  Should,  however,  it 
be  desired  to  examine  into  this  question,  the  methods  may 
be  obtained  in  Du  Bois  Reymond's  writings. 

2.  The  alterations  which  are  generally  met  with  in 
muscles  subjected  to  the  action  of  poisons  are  changes 
in  irritability,  occurring  in  various  degrees. 

Muscular  irritability  may  be  estimated  either  by  the 
direct  or  the  indirect  method.  In  general,  the  presence  of 
muscular  excitability,  as  evidenced  by  indirect  stimulation 
(^.  e.  by  nerve  irritation)  presupposes  the  existence  of  di- 
rect excitability,  although  it  is  conceivable   that  muscles 


The  nerve- iiniscle 
preparatiou.  F,  end 
of  femur ;  N,  sciatic 
nerve  ;  I,  tendo  achil- 
lis  ;  i',  origin  of  lesser 
tendon  of  gastrocne- 
mius. 


ACTION    ON    THE    MUSCLES.  87 

may  be  susceptible  only  to  stimuli  coming  through  the 
nerves.  Examination  of  indirect  muscular  excitability 
includes,  therefore,  the  examination  at  the  same  time  of 
nerve  excitability. 

1.  Examination  of  Indirect  Muscular  Irrita- 
bility.— The  general  rule  for  this  class  of  experiments 
is  that  two  muscle  preparations,  a  poisoned  and  non- 
poisoned,  must  be  continually  compared  in  order  to  elimi- 
nate changes  in  irritability  produced  by  the  drug  from 
natural  changes,  such  as  would  accompany  the  death  of 
the  nerve,  etc.  An  exception  to  this  rule  is  only  permis- 
sible when  the  changes  produced  by  the  drug  are  of  the 
most  marked  character,  sucli  as  the  production  of  entire 
loss  of  irritability. 

Both  preparations  must  be  taken  from  the  same  animal 
and  should  be  corresponding  animal  parts,  one  having 
been  previously  protected  from  action  of  the  poison  by 
ligation  of  its  bloodvessels-  The  method  has  already  been 
given.  Convulsions  or  fibrillar  contractions  caused  by 
the  operative  procedure,  must  be  allowed  to  pass  oiF  be- 
fore the^ changes  in  irritability,  if  such  exist,  are  mea- 
sured. 

Unless  there  is  some  indication  for  the  employment  of 
a  special  form  of  stimulation  [such  as  mechanical,  ther- 
mal, or  chemical],  electricity  is  always  preferable,  and 
the  most  convenient  form  is  the  tetanizing  induction  cur- 
rent. 

[For  the  ordinary  application  of  the  induced  tetanizing 
current  the  most  convenient  apparatus  is  the  Du  Bois 
Reymond  induction  coil.  This  instrument,  as  arranged 
for  use,  is  seen  in  Fig.  5.  The  positive  pole,  a;,  of  the  bat- 
tery is  connected  by  a  wire  with  the  binding  post  a, 
and  the  negative  wire,  </,  with  the  post  d;  the  current  then 
passes  through  the  vibrator  h  to  the  screw  c,  and  then 
around  the  primary  coilj^,  to  the  electro-magnets  m?w, 
the  post  c?,  and  so  back  to  the  battery  (Fig.  5).  As  soon 
as  the  current  enters  the  primary  coil  it  causes  an  instan- 
taneous induced  (closing)  shock  in  the  secondary  coil  (not 
4 


38      ACTION    OF    POISONS    ON    ISOLATED    ORGANS 


seen  in  the  figure)  ;  when  the  current  passes  around  the 
spirals  m  m,  it  renders  their  soft  iron  cores  magnetic,  and 
therefore  draws  doAvn  the  hammer  e  of  the  vibrator  /;,  and 
interrupts  the  passage  of  the  current  through  the  pri- 


Fijr.   5. 


Du  Bois  Reymond  induction  apparatus.     (From  Foster's  Physiology.)    For 
explanation,  see  text. 

mary  coil,  by  breaking  the  contact  between  h  and  c,  and 
so  causes  an  instantaneous  induced  current  (breaking 
shock)  in  the  secondary  spiral.  As  soon,  however,  as 
the  current  is  so  interrupted,  the  cores  of  m  m  lose  their 
magnetism,  the  hammer  flies  up  again,  makes  contact  with 
c,  so  allowing  the  current  to  pass,  is  again  interrupted, 
and  so  on.  The  binding  posts  on  the  secondary  coil  are 
connected  with  wires  to  the  electrodes. 

Ordinarily  it  is  sufficient  to  compare  the  strengths  of 
current  necessary  to  produce  contractions  in  the  poisoned 
and  normal  muscles.  This  can  be  done  by  first  ligating 
the  bloodvessels  of  one  hind  leg  and  then  injecting  the 


ACTION    ON    THE    MUSCLES.  39 

poison  into  the  abdominal  lymph  sac  ;  the  two  sciatic 
nerves  (or  gastrocnemii  muscles  when  direct  stimulation 
is  being  employed)  are  exposed  and  divided  high  up  ; 
their  ends  are  then  placed  on  two  pairs  of  electrodes  and 
connected,  a  double  key  (Fig.  6)  intervening,  with  the 


Pohl's  commutator  or  double  key.  (From  Sauderson's  Handbook.)  To  use 
this  instrument  as  a  double  key,  the  diagonal  wires  connecting  3  and  6,  and  4 
and  5,  are  first  removed  ;  the  binding  screws  1  and  2  are  then  connected  with  the 
secondary  coil  of  the  induction  apparatus,  and  3  and  4,  and  5  and  6,  each  with 
a  set  of  electrodes.  As  represented  in  the  figure,  the  posts  2  and  4,  and  1  and  3, 
are  electrically  connected  ;  when  the  cradle  is  rocked  so  that  its  ends  dip  in  the 
mercury  in  the  cups  at  5  and  6,  the  electrodes  connecting  with  3  and  4  are  cut 
off,  and  5  and  6  receive  the  current. 

In  order  to  use  this  instrument  as  a  current  reverser,  the  centre  wires  are 
placed  in  position  as  shown  iu  the  figure.  The  +  pole  of  the  battery  is  con- 
nected with  2  and  the  —  with  1  ;  4  consequently  is  the  -f  electrode  and  3  the 
—  electrode.  When  the  cradle  is  rocked  so  as  to  dip  into  5  and  6,  the  -f-  current 
passes  thi'ough  the  cradle  into  6,  then  across  the  connecting  wire  to  3,  which 
thus  becomes  the  4-  electrode  ;  the  —  current  follows  an  analogous  course. 

secondary  coil  of  Du  Bois  Reymond's  induction  apparatus. 
The  secondary  coil  is  then  pushed  some  distance  away 
from  the  primary  coil  (the  greater  the  distance  between 
the  coils  the  weaker  the  stimulus),  and  the  current 
closed  in  the  primary  coil  by  means  of  a  Du  Bois  Rey- 
mond  key  (Fig.  T);  if  no  contraction  is  caused  in  the 
muscle  connected  with  the  apparatus,  the  secondary  coil 
is  pushed  up  tovvards  the  primary  until  a  contraction  is 
evoked,  and  the  time  and  the  distance  between  the  two  coils 
recorded  ;  the  cradle  of  the  double  key  is  then  reversed 
so  as  to  send  the  current  through  the  other  electrodes, 
and  the  weakest  current  which  will  cause  a  contraction 


40      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

determined  in  the  same  manner.  It  may  also,  occasion- 
ally, be  well  to  determine  the  irritability  of  the  nerves 
before  the  drug  is  administered,  and  then  again  at  inter- 
vals afterwards.] 


Fiff.  7. 


Du  Bois  Reymond  key.  (From  Sanderson's  Handbook.)  When  the  wires 
are  arranged  as  represented  in  the  figure,  the  current  is  closed  iu  the  primary 
coil  by  opening  the  key,  because  when  closed  the  key,  offering  so  much  less 
resistance  than  the  coil  of  the  induction  machine,  serves  to  short-circuit  the 
current. 


If  it  be  desired  to  make  very  accurate  and  precise 
studies  as  to  the  condition  of  irritability,  especially  as  to 
the  influence  exerted  by  the  direction  of  the  current  and 
by  opening  and  closing  shocks,  another  form  of  appa- 
ratus must  be  used.  As  a  stimulus,  a  constant  galvanic 
current  is  to  be  employed,  and  the  strength  of  the  cur- 


ACTION    ON    THE    MUSCLES.  41 

rent  graduated  by  a  rheochord  ;  the  opening  and  closing 
of  the  circuit  may  be  produced  by  an  ordinary  key  or 
by  dipping  one  end  of  the  conducting  wire  into  a  cup  of 
mercury  in  which  the  other  end  of  the  wire  is  fastened, 
so  making  a  closing  shock ;  when  the  wire  is  lifted  out 
from  the  mercury,  it  of  course  being  understood  that  the 
nerve  or  muscle  is  included  in  the  circuit,  an  opening  or 
breaking  shock  is  made.  The  direction  of  the  current 
may  be  altered  by  any  of  the  various  forms  of  commu- 
tators, of  which  Pohl's  is  the  simplest.  Unpolarizable 
electrodes  should  always  be  used  ;^  while  the  height  of 
contraction  can  be  measured  by  means  of  PflUger's  myo- 
graphion. 

[The  arrangement  of  apparatus  represented  in  Fig. 
8  may  be  used  in  such  experiments.  The  induction 
coil  is  so  arranged  as  to  allow  of  either  single  opening  or 
closing  induction  shocks  being  employed.  When  the 
key  F  is  depressed,  the  current  passes  through  the 
primary  coil  by  the  two  binding  posts  on  the  top  of  the 
instrument,  without  passing  through  the  vibrator,  and  so 
produces  a  single  instantaneous  closing  shock  in  the 
secondary  coil.  When  the  key  F  is  elevated,  the  current 
ceases  to  pass  through  the  primary  coil  and  so  produces 
an  instantaneous  breaking  induction  shock.  The  wires 
from  the  secondary  coil  are  short  circuited  by  the  Du 
Bois  Reymond  key  C,  so  that  when  closed  the  key  offers 
so  much  less  resistance  than  the  wires  and  parts  beyond 
that  no  current  reaches  the  electrodes.  If,  therefore,  it 
is  desired  to  pass  a  single  closing  shock  through  the 
nerve  or  muscle,  the  key  C  is  first  opened  and  then  the 
key  F  closed,  and  the  key  C  is  then  closed  before  the 
key  ^  is  opened;  if  a  single  breaking  shock  is  desired, 
the  key  C  is  first  closed  and  then  the  key  F ',  and  while 
the  latter  is  closed  the  former  is  opened,  and  then  the 
current  through  the  primary  coil  broken  by  elevating  F, 
A   represents   a  convenient  form  of  moist  chamber  in 

'  Rosenthal,  Electricitatslehre,  2  Aufl.  57.     A  simpler  form  is  de- 
scribed by  Hermann,  Arobiv  f.  d.  Gesamt.  Physiol,  iv.  211. 

4* 


42      ACTION    OF    POISONS    ON    ISOLATED    ORGANS 


.^'. 


w 


iiiiiiii 


oo 


.ViJL>- 


a    a 


ACTION    ON    THE    MUSCLES, 


4B 


which  the  preparation  is  prevented  from  drying  by  cover- 
ing the  bottom  of  the  chamber  with  layers  of  filter  paper 
moistened  with  normal  salt  solution,  while  evaporation  is 
prevented  by  the  glass  shade.  The  nerve-muscle  prepa- 
ration and  a  convenient  form  of  electrodes  are  shown  on  a 
larorer  scale  in  Fig.  9.     Below  the  moist  chamber  is  seen 

Fig.  9. 


Enlarged  repieseutatiou  of  holder  aud  electrodes  seen  in  Fig.  8. 
(From  Foster's  Physiology.) 

a  simple  loaded  lever  by  which  the  height  of  muscular 
contraction,  or  the  form  of  the  muscle-curve,  can  be  studied 
by  allowing  it  to  record  its  movements  on  the  smoked 
paper  of  the  revolving  drum  of  the  kymographion.  In- 
stead of  the  simple  lever,  which  will  of  course,  when  ele- 
vated, describe  an  arc  of  a  circle,  Pfiliger's  myographion 
lever  (Fig.  10)  may  be  employed.  In  very  accurate 
experiments  non-polarizable  electrodes  should  be  used 
(Fig.  11).  These  are  readily  made  by  plugging  up  one 
end  of  a  short  piece  of  glass  tubing  a,  with  clay,  ^,  mois- 
tened with  normal  salt  solution  ;  a  few  drops  of  saturated 
solution  of  sulphate  of  zinc  are  then  poured  into  the  tube 
as  seen  at  <?,  care  being  taken  that  none  flows  over  the 
outside,  and  a  strip  of  zinc,  well  amalgamated  at  the  tip 
and  insulated  by  varnish  over  the  remainder  of  its  length, 
is  dipped  into  the  zinc  solution.     The  wires    from  the 


44      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

battery  are  connected  with  the  zinc ;  the  electrodes  may 
be  conveniently  held  on  pieces  of  heavy  lead  wire. 

Fig.  10. 


Pfluger's  myographion.  (From  Sanderson's  Handhook.)  The  lever  a  moves 
freely  on  the  fulcra  6  6  ;  at/  is  hung  the  swinging  rod  e,  with  the  movable 
style  (i,  and  movable  counterpoise  ^;  at  c  is  a  heavy  counterpoise  to  balance 
the  lever.     The  tendon  is  connected  with  the  lever  by  the  thread  h. 

In  many  cases  when  the  drug  produces  slight  changes 
in  the  muscle  curve,  Marey's  comparative  myograph  is 

Fiff.  11. 


Non-polarizable  electrode. 


the  most  satisfactory  instrument  that  can  be  employed ; 
the  mode  of  using  it  is  represented  in  Fig.  1 2.     A  frog 


ACTION    ON    THE    MUSCLES. 


46 


is  fastened  on  its  bellj  with  pins,  and  the  tendon  of  each 
gastrocnemius    connected    by    a    thread    with    a   lever 


Fi-.  12. 


Marey's  comparative  myograph. 

which  writes  on  the  revolving  cylinder :  the  artery  of 
one  leg  is  then  ligated  and  the  poison  injected  into  the 
body,  and  the  muscle-curves,  obtained  by  stimulating  the 
poisoned  and  normal  muscle,  compared.  The  effects  on 
the  muscle  in  relation  to  indirect  stimulation  can  also  be 
studied  by  exposing  the  sciatic  nerves  and  applying  the 
electrodes  to  them  instead  of  directly  stimulating  the 
muscle.] 

In  many  cases  where  it  is  desired  to  determine  simply 
the  presence  or  absence  of  irritability,  all  that  is  neces- 
sary is  to  lay  the  nerve  of  the  poisoned  preparation  on 
electrodes  connected  with  an  induction  apparatus  through 
which  a  strong  current  is  passing.  In  many  experiments 
the  irritation  may  even  be  made  by  means  of  a  small 
galvanic  element  consisting  of  a  zinc  and  copper  wire 
fastened  to^^ether  with  a  bindinor  screw  :^  stimulation  is 


^  Da  Bois  Reymond,  TTiitersucliuiigen,  1  Taf.  iii.  fig.  19. 


46      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

then  produced  by  making  or  breaking  the  contact  be- 
tween the  wires  and  the  nerve. 

2.  Examination  of  Direct  Muscular  Irritability. 
— This  form  of  examination  is  only  indicated  when  the  in- 
direct irritability  is  either  entirely  absent  or  greatly  re- 
duced. Muscles  may  be  directly  stimulated,  either 
mechanically,  chemically  (as  by  immersion  in  very  dilute 
acid),  or  electrically,  as  by  bringing  the  electrodes  of  an 
induction  apparatus  in  contact  with  an  isolated  or  ex- 
posed muscle.  The  rule  in  this  case  is  to  have  the  elec- 
trodes as  widely  separated  as  possible :  therefore  the 
most  convenient  form  of  electrode  consists  of  two  flexible 
insulated  wires  with  their  tips  exposed,  passed  through 
a  few  inches  of  flexible  catheter  and  fastened  together  so 
that  about  one  inch  of  their  free  ends  protrudes. 

In  all  cases  of  direct  irritation  of  a  muscle,  the  nerve 
fibres  lying  in  the  muscle  are  also  subjected  to  the  same 
stimulation.  If  then  direct  stimulation  of  a  muscle  pro- 
duces a  contraction,  even  when  indirect  stimulation  fails, 
the  contraction  may  be  due  to  irritation  of  the  intra-mus- 
cular  nerve-fibres,  since  the  nerve  endings  may  preserve 
their  irritability  even  after  paralysis  of  the  nerve  trunks. 
By  an  experiment  devised  by  Ktihne^  it  may  be  deter- 
mined whether  this  nerve  irritability  remains  or  not,  it 
being  supposed,  of  course,  that  the  muscle  itself  still  pre- 
serves its  irritability. 

In  the  sartoi'ius  of  the  frog,  the  nerve  enters  the 
muscle  at  its  middle  point,  and  sends  branches  towards 
each  end,  but  leaves  a  small  portion  at  both  extremities 
of  the  muscle,  near  the  tendon,  entirely  free  from  nerves. 
If  now  a  pair  of  electrodes,  of  which  the  tips  are  very 
close  together,  are  connected  with  an  induction  appa- 
ratus, and  then  placed  perpendicularly  on  the  centre  of 
a  normal  sartorius,  it  will  be  found  that  a  much  weaker 
current  will  suffice  to  evoke  contractions  when  the  elec- 
trodes are  at  this  point,  than  when  they  are  over  the  por- 

1  Arch.  f.  Anat.  u.  Physiol.,  1860,  477. 


ACTION    ON    THE    MUSCLES.  47 

tions  of  the  muscle  near  the  tendon,  which  are  free  from 
nerves.  This  indicates  that  the  irritability  of  the  nerves 
is  greater  than  that  of  muscle-fibre.^ 

If  now,  in  a  poisoned  muscle,  it  is  found  that  the  dif- 
ference in  irritability  at  different  points  of  the  muscle  is 
absent,  or  is  much  less  marked  than  in  a  normal  muscle,  it 
may  be  concluded  that  the  intra-muscular  nerve-endings 
have  lost  their  excitability,  or  that  it  has  been  much 
reduced. 

3.  Examination  of  the  Physiological  Conductiv- 
ity OF  Muscle. — When  a  normal  muscular  fibre  is  irri- 
tated at  a  single  point,  the  resulting  contraction  travels 
with  great  rapidity  throughout  its  entire  length.  In 
order  to  determine  whether  the  muscle,  when  poisoned, 
still  preserves  the  property  of  transferring  the  contraction 
throughout  its  entire  length,  a  form  of  stimulation,  such 
as  the  mechanical,  in  which  the  stimulating  effect  is  con- 
fined to  a  small,  sharply  defined  area,  must  be  selected  ; 
the  experiment  is  also  assisted  when  the  simultaneous 
irritation  of  the  intra-muscular  nerve-fibre  is  excluded. 
The  portion  of  the  sartorius  which  is  free  from  nerves  is 
therefore  well  adapted  to  the  investigation  of  this  point. 
The  poison  is  administered  to  a  frog,  and,  when  its  effects 
become  evident,  the  sartorius  is  isolated  and  suspended 
in  an  inverted  position  by  its  tendon  of  insertion,  and  the 
lower  end  of  the  muscle,  near  its  point  of  origin  where  it 
is  also  free  from  nerves,  divided  transversely  with  a  pair 
of  sharp  scissors  ;  if  the  muscle  is  in  its  normal  condition, 
the  mechanical  stimulation  of  section  with  the  scissors 
will  cause  it  to  contract  throughout  its  entire  length. 

Studies  as  to  changes  in  the  rate  of  progression  of  the 
wave  of  contraction  necessitate  a  complicated  method,  for 
which  the  appropriate  literature  must  be  consulted.^ 

'  Eosentlual,  Molescliott's  Uutersnchungen,  iii.  185. 

2  See  Albey,  Untersuchungen  ilber  die  Fortpflaiizungsgescli- 
windigkeit,  etc.,  Braunschweig,  1862.  Bernstein,  Untersuch- 
ungen liber  die  Erregungsvorgang,  etc.     Heidelberg,  1871-78. 


48       ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

4.  Measurement  of  Muscular  Energy. — For  this 
purpose  comparative  experiments  must  always  be  made 
on  both  poisoned  and  non-poisoned  muscles,  and  it  is  ad- 
visable to  employ  excessively  strong  induction  (tetaniz- 
ing)  currents,  since  both  muscles  must  not  only  be  sub- 
jected to  the  same  stimulation,  but  must  be  stimulated 
sim.ultaneously. 

When  it  is  not  intended  to  measure  the  absolute 
energy,  the  muscle  may  be  loaded  with  a  medium-sized 
weight  (about  20  grms.  for  the  gastrocnemius),  and  the 
height  to  which  the  muscle,  with  a  given  stimulus,  can 
raise  the  weight,  determined  ;  then  the  weight  is  hung  on 
the  second  muscle  which  is  to  be  compared  Avith  the  first, 
and  the  height  of  contraction,  with  the  same  stimulus, 
measured.  The  measurement  of  the  height  of  contrac- 
tion is  most  easily  made  by  means  of  Pflliger's  Myo- 
graphion.^ 

An  immediate  comparison  of  the  energy  of  tAvo  simi- 
lar muscles  may  be  made  by  hanging  them  alongside  of 
one  another  and  connecting  their  tendons  with  threads 
from  which  equal  weights  are  suspended  ;  the  threads  are 
then  wrapped  once,  in  opposite  directions,  around  a  small 
pulley  (a  spool  will  do)  furnished  with  a  vertical  index  ; 
when  both  muscles  are  simultaneously  stimulated  with 
the  same  current,  the  index  will  move  toward  the  weaker 
muscle.^ 

6.  Examination  of  Alterations  in  the  Chemical 
Properties  of  Muscle. — Little  more  can  be  noted  in 
this  connection  than  the  determination  of  the  degree 
of  rigidity  of  the  muscle  and  of  its  reaction  ;  both,  of 
course,  can  only  be  taken  into  consideration  when  the 
muscle  has  completely  lost  its  irritability.  Rigor  is 
easily  recognized  by  the  eye,  especially  when  the  thin- 
ner muscles  are  examined  by  transmitted  light,  since  mus- 
cles in  a  condition  of  rigor  become  opaque ;  muscles  in 

'  Pfliiger,  Electrotoinis.     Berlin,  1859,  Taf.  iii. 
2  Herrnatin,    Diss,    de    Tono   et    Motor    Muscul.,   Berlin,   1859; 
Nasse,  Arch.  f.  d.  ges.  Phys.,  ii.  97. 


ACTION    ON    THE    NERVES.  49 

a  condition  of  rigor  also  lose  their  flexibility,  and  their 
rigidity  could  never  be  mistaken  for  convulsions.  The 
most  unmistakable  sign  of  rigor,  however,  is  the  acid  re- 
action developed,  which  can  be  readily  recognized  by 
touching  a  freshly  cut  surface  of  muscle  with  blue  lit- 
mus paper.  A  general  idea  as  to  which  of  the  albumi- 
noids of  muscles  have,  by  their  coagulation,  produced  the 
rigor,  may  be  obtained  by  immersing  the  rigid  muscle  in 
10  per  cent,  salt  solution  ;  if  produced  by  the  coagula- 
tion of  the  spontaneously  coagulable  albuminoid  myosin, 
the  muscle  will  regain  its  normal  flexibility,  myosin  be- 
ing soluble  in  salt  solution  ;  but  if  due  to  the  coagulation 
of  the  albuminoids,  which  ordinarily  are  coagulated  only 
by  heat,  acids,  etc.,  no  such  change  will  be  produced. 

The  color  of  the  muscles  should  also  be  observed,  as 
capable  of  throwing  some  light  on  the  degree  of  im- 
pregnation with  coloring  matters  and  thereby  giving 
some  idea  of  changes  occurring  in  the  latter.'^ 

For  investigation  as  to  this  point,  the  blood  must  first 
be  washed  out  of  the  bloodvessels  of  the  muscles  by  in- 
jecting them  with  0.5  per  cent,  salt  solution.  The  qualita- 
tive examination  of  the  muscle  coloring  matters  (as  to  their 
percentage  of  oxygen,  etc.),  may  be  made  by  placing 
thin  sections  of  muscle  between  two  glass  plates  and 
then  bringing  them  before  the  slit  of  the  spectroscope. 

For  more  precise  study  of  changes  in  the  chemical 
composition  of  muscle,  no  general  rules  can  be  given. 


Section  III. — Action  on  the  Nerves. 

With  the  exception  of  studies  relating  to  the  electro- 
motor phenomena  of  nerves,  to  which  the  remarks  on 
the  study  of  the  same  points  in  muscles  apply,  iso- 
lated nerves  need  only  be  examined  with  reference  to 
their  power  of  transmitting  motor  impulses  to  the  mus- 
cles in  which  they  terminate. 

'  Kiihne,  Arch.  f.  Path.  Anat.,  xxxiii.  79. 
5 


50      ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

Possibly  the  examination  as  to  the  functions  of  secre- 
tory nerves,  when  excised  with  their  glands,  may  be 
necessary  to  determine,  by  exclusion,  what  part  of  the 
results  following  their  stimulation  is  not  due  to  the  pre- 
sence or  modification  of  their  blood  supply.  All  cen- 
tripetal (sensory)  nerves,  on  the  other  hand,  can  be 
studied  only  in  connection  with  the  central  nervous  sys- 
tem and  its  dependent  motor  apparatus,  and  their  con- 
sideration must,  therefore,  be  reserved  for  the  chapters  on 
the  living  animal,  in  which  their  modifications  are  also 
evidenced  through  changes  in  the  character  of  reflexes. 

At  present,  changes  in  excised  motor  nerves  alone  will 
be  considered. 

The  examination  of  the  irritability  of  motor  nerves  has 
already  been  alluded  to  in  the  study  of  indirect  muscu- 
lar irritability.  In  order  to  obtain  any  idea  as  to  the 
state  of  irritability  of  a  motor  nerve,  the  muscle,  with 
which  it  is  in  connection,  must  of  course  preserve  its 
contractility  unimpaired,  or  irritation  of  the  nerve  will 
be  powerless  to  produce  a  contraction,  and  therefore 
no  comparison  of  its  irritability  with  a  normal  standard 
will  be  possible.  If,  however,  the  drug  under  exami- 
nation produces  paralysis  of  muscular  fibres,  the  poison, 
while  having  free  access  to  the  nerve,  must  be  pre- 
vented from  acting  on  the  muscle  ;  this  may  be  accom- 
plished by  ligating  the  femoral  artery  in  one  leg  of  a 
frog,  near  the  knee  (see  p.  33),  before  the  drug  is  ad- 
ministered, thus  protecting  the  muscles  of  the  leg  from  the 
poison.  The  sciatic  nerve  may  then  be  tested  as  to  its 
irritability  with  some  prospect  of  reliable  results.  The 
readier  method  of  immersing  the  nerve  of  an  unpoisoned 
animal  in  the  solution  of  tlie  drug  is  unreliable,  on  ac- 
count of  the  grounds  mentioned  on  page  31,  and  results 
obtained  by  this  method  should  be  accepted  with  the 
greatest  caution. 

If  it  has  been  determined  that  the  drug  has  no  influ- 
ence on  direct  muscular  irritability,  or  if  the  irritability 
of  the  muscle  has  been  maintained  in  the  manner  men- 
tioned above,  and  it  is  then  found  that  stimulation  of  the 


ACTION    ON    THE    NERVES.  51 

nerve  fails  to  evoke  a  muscular  contraction,  the  question 
then  remains,  what  portion  of  the  nerve,  between  the 
point  of  stimulation  and  its  termination  in  the  muscular 
fibre,  has  lost  its  function  and  thereby  prevents  the  normal 
result  of  nerve  stimulation?  To  appreciate  the  force  of 
this  it  is  only  necessary  to  remember  that  every  unirri- 
table  point  in  a  nerve  trunk  is  at  the  same  time  an 
obstacle  to  the  conduction  of  nerve  force  ;  and  in  order 
to  render  a  stimulation  of  a  nerve  of  no  effect,  it  is  only 
necessary  that  any  limited  portion  of  the  nerve  below 
the  point  of  application  of  the  stimulus  should  have  lost 
its  irritability.  To  detect  this  point,  therefore,  succes- 
sive points  of  the  nerve  are  stimulated,  gradually  moving 
the  electrodes  down  toward  the  muscle,  until  a  contrac- 
tion is  produced,  when  it  is  known  that  the  paralyzed 
point  has  been  passed.  If,  however,  stimulation  of  the 
nerve  (with  a  weak  current)  at  its  point  of  entrance  into 
the  muscle  fails  to  produce  a  contraction,  it  is  evident, 
by  exclusion,  that  the  intra-muscular  nerve  filaments  must 
be  paralyzed.  This  supposition,  again,  may  be  verified 
by  the  mode  of  experimentation  on  the  frog's  sartorius, 
given  on  page  46. 

Through  the  method  given  above  only  the  lower  limit 
of  the  region  of  paralysis  can  be  determined ;  for  the 
detection  of  the  upper  limit  of  paralysis  of  the  nerve,  no 
modification  of  this  method  of  study,  in  which  the  con- 
traction of  the  muscle  is  a  measure  of  the  irritability  of 
the  nerve,  has  yet  been  proposed. 

The  irritability  of  a  nerve-fragment  may  be  determined, 
without  the  use  of  its  muscle,  by  the  presence  of  the 
negative  variation  of  the  nerve  current.  When  a  normal 
nerve  is  irritated  the  natural  nerve  current  suff"ers  a 
negative  variation  on  both  sides  of  the  point  of  stimula- 
tion, and  through  as  great  an  extent  of  nerve  as  preserves 
its  irritability.  [This  experiment  is  made  by  preparing 
as  long  a  piece  of  sciatic  nerve  as  possible  and  resting 
the  cross  section  of  the  peripheral  end  on  one  non-polar- 
izable  electrode  connected  with  a  very  sensitive  galvano- 
meter, while  the  other  electrode  is  placed  on  its  longi- 


52       ACTION    OF    POISONS    ON    ISOLATED    ORGANS. 

tudinal  surface  at  some  distance  above  ;  another  pair  of 
electrodes,  connected  with  a  tetanizing  apparatus,  is 
then  placed  on  the  nerve  as  far  as  possible  removed  from 
the  galvanometer  electrodes.  If  now,  on  passing  a 
current  through  the  exciting  electrodes,  the  deflection  of 
the  galvanometer  needle  caused  by  the  nerve  current 
does  not  undergo  a  negative  variation,  it  may  be  known 
that  the  paralyzed  point  lies  somewhere  between  the 
electrodes  ;  its  exact  limits  may  be  determined  by  shift- 
ing the  electrodes.] 

This  method  is  therefore  not  only  applicable  here,  but 
also  to  the  study  of  changes  of  irritability  in  sensory 
nerves. 


Section  IV.— Action  on  the  Heart. 

[Of  the  other  remaining  organs  which  are  capable  of 
isolated  study,  the  heart  is  the  most  important  and  is 
the  organ  Avhich  has  received  the  greatest  attention  ;  its 
study  in  detail  will,  however,  more  appropriately  be 
taken  up  under  the  study  of  the  circulation.  At  present 
we  will  only  indicate  the  methods  of  experiment  which  can 
be  performed  as  an  introduction  to  the  more  extended 
analysis  of  the  action  of  the  drug  on  the  circulatory  ap- 
paratus. 

When  kept  in  a  moist  atmosphere  the  irritability  of 
the  excised  frog's  heart  and  its  regulating  nerves  may  be 
preserved  for  hours  ;  the  frog  is  therefore  the  animal 
which  is  selected  for  these  preliminary  studies,  though 
the  heart  of  the  turtle,  which  also  possesses  these  proper- 
ties, may  be  used. 

Changes  in  the  rate  of  cardiac  pulsation,  the  only 
point  which  will  be  now  considered,  may  be  determined 
in  one  of  two  ways :  Either  the  drug  may  be  applied  to 
the  heart  in  situ,  after  destruction  of  the  central  nervous 
system,  or  the  heart  may  be  excised  and  then  brought 
under  the  influence  of  the  poison. 

To  perform  the  first  of  these  experiments  the  frog  is 


ACTION    ON    THE    HP]ART.  53 

"pithed"  by  cutting  through  the  vertebral  column  imme- 
diately below  the  occipital  bone  and  breaking  up  the  cen- 
tral nervous  system  by  passing  a  stout  wire  up  and  down 
the  vertebral  canal ;  this  operation  should  be  so  per- 
formed that  little  or  no  blood  is  lost.  Should  any 
bleeding  occur,  it  may  be  checked  by  driving  a  small 
wooden  peg  into  the  cranium  through  the  wound  in  the 
vertebral  column.  The  frog  is  then  laid  on  its  back  and 
the  skin  divided  with  scissors  in  the  median  line,  and  the 
sternum  and  the  upper  anterior  part  of  the  visceral  wall 
removed  so  as  to  expose  the  pericardium,  care  being 
taken  not  to  injure  the  large  abdominal  vein  which  runs 
in  the  median  line  on  the  anterior  surface  of  the  abdomi- 
nal wall.  The  heart  is  then  seen  lying  in  the  pericar- 
dial sac,  and  its  rate  of  pulsation  can  be  counted.  A 
snip  is  then  made  in  the  pericardium',  and  the  pericardial 
sac  filled,  by  means  of  a  pipette,  with  the  solution  of  the 
drug,  and  any  changes  in  the  cardiac  rhythm  noted. 

For  studies  on  the  action  of  drugs  on  the  rate  of  pul- 
sation of  the  excised  heart,  two  frogs  of  the  same  species 
and  of  nearly  the  same  size  should  be  selected,  and  the 
hearts  exposed  in  the  manner  above  described  ;  the  hearts 
are  then  excised  by  cutting  through  all  the  cardiac  vessels, 
care  being  taken  not  to  injure  the  sinus  venosus,  or  any  of 
the  chambers  of  the  heart.  One  heart  is  then  placed  in 
a  watch-glass  containing  normal  salt  solution,  and  the 
other,  after  its  rate  of  beating  has  been  determined,  in 
the  solution  of  the  poison  ;  the  changes  in  the  rates  of  pul- 
sation of  the  two  hearts  are  then  compared.]  It  should 
be  remembered  that  many  gases,  if  the  drug  employed  is 
of  such  nature,  and  they  are  more  suitable  for  this  form 
of  experiment  than  are  solutions,  exert  a  more  decided 
action  when  locally  applied  than  when  acting  through 
the  blood. 


5* 


PART  II. 

INVESTIGATION  OF  THE  GENERAL  ACTION 
OF  POISONS. 


I. 

SELECTION  OF  ANIMALS. 

The  general  rules  given  in  this  section  have  been 
drawn  from  the  accumulated  experience  of  previous  ex- 
perimentation, and  though  they  may  serve  as  a  starting 
point  for  future  investigations,  they  cannot  be  regarded 
as  infallible.  This  reservation  is  especially  applicable 
to  indications  given  for  the  selection  of  animals  as  sub- 
jects for  experimentation,  since  future  investigations 
may  show  that  many  animals,  now  regarded  as  unsuit- 
able for  the  experimental  study  of  the  action  of  poisons, 
may  prove  to  be  particularly  valuable  for  the  determina- 
tion of  special  points. 

The  invertebrates,  the  warm-  and  cold-blooded  verte- 
brates, or  man,  may  serve  as  subjects  for  the  investiga- 
tions of  the  properties  of  drugs.  Among  these,  the  cold- 
blooded vertebrates  are  the  most  generally  employed,  and 
the  same  peculiarities  which  have  made  the  frog  a  martyr 
to  physiology  make  him  subject  to  martyrdom  in  the 
cause  of  pharmacology.  For  not  only  may  the  frog 
withstand  the  most  severe  operations,  but  also  nearly 
all  its  organs  may  be  removed  from  the  circulation  and 
still  preserve  their  functions  unaltered. 

In  the  warm-blooded  animals,  all  poisons  which,  through 
action  on  the  heart,  interfere  with  the  circulation,  or 
which,  through  interference  with  respiration,  alter  the 
proportion  of  gases  in  the  blood,  at  the  same  time  pro- 


56  GENERAL    ACTION    OF    POISONS. 

duce  extensive  alteration  in  the  functions  of  all  organs ; 
while  the  same  drags  administered  to  frogs  may  fail  to 
produce  any  general  disturbance,  particularly  in  the  ner- 
vous system  or  muscles.  When,  therefore,  after  the 
administration  of  any  poison,  departures  from  the  normal 
functions  are  observed  in  the  muscular  or  nervous  system 
of  the  frog,  they  may  be  ascribed  with  certainty  to  the 
direct  action  of  the  poison  on  these  organs,  without  the 
possibility  of  their  being  attributable  to  some  secondary 
reaction  following  from  disturbance  in  the  circulatory  or 
respiratory  apparatus,  or  in  changes  in  the  respiratory 
functions  of  the  blood.  In  the  closest  connection  with 
this  peculiarity  of  the  frog,  may  be  mentioned,  as  has 
been  already  alluded  to  in  the  preceding  pages,  the 
possibility  of  excising  or  excluding  from  the  circula- 
tion (the  latter  of  the  greatest  importance,  where  it  is 
desired  to  protect  certain  tissues  from  the  action  of  the 
poison)  the  various  organs  of  the  frog  without  their 
suffering  any  profound  disturbance  in  function.  If  any 
further  advantages  were  needed,  it  might  be  added  that 
in  frogs  the  heart  is  extremely  easy  to  expose,  and  that 
the  circulation  is  readily  accessible  for  microscopic 
study. 

Nevertheless,  the  investigation  of  the  action  of  all 
poisons  on  warm-blooded  animals  is  in  the  highest  degree 
important.  The  essential  object  of  pharmacology  is  in  all 
cases  a  recognition  of  the  action  of  poisons  on  man,  and 
it  cannot  be  denied  that  experiments  on  warm-blooded 
animals  furnish  means  of  deducing  more  reliable  conclu- 
sions as  to  this  point  than  when  made  on  frogs.  In  addition 
the  following  reasons  render  advisable,  on  physiological 
grounds,  the  study  of  poisons  on  mammals.  In  the  first 
place,  the  small  size  of  many  organs  in  the  frog,  such  as 
the  diff'e rent  glands,  renders  an  accurate  study  impossible  ; 
while  in  the  larger  mammals  the  ducts  of  most  of  the 
glands  are  readily  isolated,  and  the  secretions  measured 
and  obtained  in  sufficient  amount  for  chemical  examina- 
tion. Then  the  location  of  deposit  of  poisons  in  the  sys- 
tem, their  excretion,  and  the  chemical  changes  which  they 


SELECTION    OF    ANIMALS.  57 

undergo,  can,  on  account  of  the  quantities  of  material 
necessary  for  chemical  study,  only  be  determined  in  the 
larger  animals.  While,  therefore,  on  these  grounds, 
warm-blooded  animals  as  a  class  are  required  for  the 
thorough  study  of  the  modus  operandi  of  poisons,  as  a 
rule  it  makes  no  difference  which  members  of  this  class, 
with  certain  special  exceptions  to  be  hereafter  men- 
tioned, are  chosen.  Before  all  things,  however,  it  must 
be  emphasized  that  the  general  action  of  all  poisons 
which  act  either  on  the  blood,  the  heart,  or  the  respira- 
tion, may  differ  in  the  most  marked  degree,  even  when 
the  action  on  individual  organs  closely  corresponds ; 
this  is  readily  explainable  on  the  grounds  already  men- 
tioned, and  the  points  of  difference  will  be  subsequently 
more  closely  studied. 

Then  again,  there  are  many  poisons  which  have  a 
different  action  on  different  groups  of  animals,  and  to 
obtain  a  complete  idea  of  the  action  of  such  poisons, 
various  types  of  animals  must  of  course  be  experi- 
mented on. 

These  are  then  the  chief  points  which  render  the  warm- 
blooded animals  indispensable  for  pharmacological  studies. 
From  what  has  been  said  it  follows  that  the  last  of  the 
above-mentioned  points  may  be  worked  out  on  the  smaller 
animals,  such  as  small  birds,  pigeons,  mice,  rats,  guinea- 
pigs,  etc.,  while  the  larger  mammals,  such  as  cats,  rab- 
bits, dogs,  or  horses,  besides  being  more  easily  operated 
on,  are  best  suited  for  the  first- mentioned  purposes. 

For  example,  suppose  that  we  are  dealing  with  a 
poison  which  has  been  found  to  paralyze  the  muscles  of 
respiration  in  frogs,  and  in  mammals,  in  addition  to 
the  respiratory  paralysis,  to  cause  convulsions  ;  it  must 
then  be  determined  whether  the  convulsions  are  only 
secondary  to  the  interference  with  respiration ;  this 
would  explain  their  absence  in  the  case  of  the  frog. 
The  simple  experiment  of  artificial  respiration  will  de- 
cide this  in  the  case  of  the  mammal,  since  the  removal 
or  prevention  of  the  respiratory  disturbance,  in  such  in- 


58  GENERAL    ACTION    OF    POISONS. 

stances,  will  remove  or  suspend  the  cause  of  the  convul- 
sions. 

Then  too,  measurements  of  blood  pressure  and  the 
intravenous  injection  of  poisons,  can  be  readily  practised 
only  on  the  larger  mammals. 

On  these  grounds,  therefore,  rabbits  and  dogs  are  the 
examples  of  warmblooded  animals  ordinarily  used  for 
pharmacological  pu rposes .  They  furnish  representatives  of 
the  two  groups  of  the  herbivora  and  carnivora,  on  which 
many  drugs  act  in  diiferent  degrees  of  intensity.  Cats, 
on  account  of  their  cheapness,  would  be  largely  preferred 
to  dogs,  if  experimenting  on  them  was  less  unpleasant. 
Horses,  unfortunately,  can  be  but  rarely  obtained  for 
pharmacological  work ;  hens,  as  large  and  cheap  respresen- 
tatives  of  birds,  are  very  valuable  for  the  study  of  many 
points,  though  it  must  be  remembered  that  many  poisons, 
e.  g.^  strychnia,  act  in  different  degrees  on  birds  and 
mammals,  on  account  of  the  chemical  diversities  in  the 
renal  secretions  of  these  animals.  The  smaller  animals, 
such  as  mice,  rats,  guinea-pigs,  and  pigeons,  may  be  used 
to  determine  the  general  action  of  the  poison  on  warm- 
blooded animals.  Other  animals  may  on  special  grounds 
be  valuable  subjects  for  study  ;  such  as  the  bat,  on  ac- 
count of  its  pulsating  wing-vessels,  rabbits  on  account  of 
the  readiness  with  which  the  circulation,  especially  after 
depilation,  may  be  studied  in  the  vessels  of  the  ear,  and 
albino-rabbits  on  account  of  the  peculiarity  of  their  eyes. 

Associated  with  experimentation  on  warm-blooded 
animals,  the  determination  of  the  action  of  most  poisons 
on  man  is  of  the  highest  interest,  since  in  man  only 
can  the  group  of  phenomena  produced  by  action  on 
the  sensory  apparatus  be  studied  with  any  prospect  of 
obtaining  reliable  results  ;  any  correct  idea  as  to  toxico- 
logical  doses,  data  of  the  greatest  practical  importance, 
moreover,  cannot,  as  a  rule,  be  obtained  from  experi- 
ments on  animals.  All  modifications  of  sensibility  and 
consciousness,  and  possibility  of  voluntary  motion,  can  be 
examined  in  experiments  on  ourselves,  and  the  results 
recorded  either  during  the  experiment  or  from  memory 


SELECTION    OF    ANIMALS.  69 

afterwards,  or  experiments  can  be  made  on  another  and 
the  results  communicated  during  the  course  of  the  experi- 
ment. At  the  best,  however,  the  comparison  between 
the  drugged  and  normal  condition,  though  more  reliable 
than  similar  modes  of  investigation  on  animals,  is  apt  to 
be  very  deceptive. 

The  invertebrate  animals  have  as  yet  been  very  seldom 
employed  in  pharmacological  studies  ;  general  rules  as 
to  the  condition  in  which  they  are  suitable  cannot,  there- 
fore, be  given,  it  being,  however,  understood  that  since 
these  animals  only  possess  haemoglobin  in  exceptionally 
small  quantities,  they  cannot  be  used  for  the  study  of 
drugs  which  act  on  that  tissue. 

From  the  above  it  may  be  concluded  that  methodical 
investigations  of  the  action  of  a  poison  should  commence 
with  experiments  on  frogs,  and  then  on  warm-blooded 
animals,  and  later,  in  suitable  cases,  on  man,  if  the  cases 
of  poisoning  which  have  been  recorded  in  the  case  of 
nearly  all  poisons  do  not  sufficiently  clear  up  those  points 
which  are  alone  suitable  for  study  on  man. 

[The  important  position  recently  assumed  by  the  lower 
organisms,  such  as  bacteria  and  bacilli,  in  disease  pro- 
cesses, renders  it  advisable  to  test  the  action  of  all  new 
drugs,  and  drugs  imperfectly  understood,  on  these  organ- 
isms ;  but  since  the  whole  subject  is  at  present  in  a 
transitory  condition,  little  more  than  an  outline  of  a  few 
rudimentary  experiments  can  be  given. 

The  action  on  human  protoplasm  may  be  assumed  to 
have  been  already  studied  with  the  white  blood-corpus- 
cles ;  protoplasm  in  lower  forms  may  be  studied  in  the 
action  of  drugs  on  the  amoeba,  often  to  be  found  in 
moist,  damp  earth,  or  on  infusoria,  found  in  great  variety 
in  all  fresh-water  infusions  of  decaying  animal  or  vege- 
table matter.  The  limit  of  study  drawn  by  our  present 
lack  of  knowledge  lies  in  determining  whether  the  move- 
ments of  the  infusoria,  bacteria,  etc.,  are  checked  by  the 
drug,  or  whether  the  drug  furnishes  a  good  medium  for 
their  development ;  or,  perhaps,  it  may  be  found  that 
certain  substances  added  to  the  culture  fluids  in  which 


60  GKNERAL    ACTION    OF    POISONS. 

the  specific  bacilli  or  micrococci  are  being  developed, 
may  destroy  their  virulence  Nvithout  destroying  their 
life,  or  may  entirely  prevent  their  appearance. 

Infusoria  may  be  obtained  in  great  variety  and  num- 
bers by  making  an  infusion  of  hay,  or  other  vegetable 
matter,  and  allowing  it  to  stand  for  several  days  in  the 
open  air.  A  drop  of  the  fluid  is  then  withdrawn  with  a 
pipette  and  placed  on  a  microscopic  slide,  covered  with 
a  slip,  and  examined  ;  after  infusoria  in  active  motion  are 
found,  a  drop  of  the  solution  is  run  in  under  the  edge  of 
the  cover-slip,  and  the  field  again  examined  to  see  if  the 
infusoria  are  still  moving.  If  they  appear  unchanged, 
a  drop  of  a  stronger  solution  is  passed  in,  and  the  field 
again  examined,  and  so  on,  until  the  necessary  strength 
of  solution  is  determined,  or  until  it  is  proved  that  the 
drug  is  without  effect.  If  the  substance  experimented 
with  should  be  a  gas,  a  drop  of  the  infusion  should  be 
placed  on  a  cover-slip,  and  the  latter  placed  on  Strieker's 
gas  chamber,  which  is  to  be  used  in  the  ordinary  manner. 

As  discovered  by  Binz,  certain  substances,  such  as 
various  salts,  may  destroy  the  life  of  infusoria  by  the 
abstraction  of  water  which  they  cause,  while  others,  par- 
ticularly such  substances  as  are  known  as  antiseptics, 
destroy  low  forms  of  life  in  some  unknown  manner. 

Bacteria  and  vibrios  may  be  readily  obtained  in  infu- 
sions of  putrefying  animal  matter,  such  as  boiled  white 
of  egg,  or  meat,  and  the  influence  of  drugs  upon  them 
may  be  tested  in  the  same  manner  as  on  infusoria.] 


Modes  of  Securing  Animals. 

[Nearly  all  the  methods  of  investigation  of  the  action 
of  drugs  hereafter  to  be  described  require  that  the  ani- 
mals, on  which  the  experiments  are  made,  should  be 
prevented  from  moving.  This  restraint  may  be  of  two 
kinds,  either  mechanical  or  chemical.  The  latter  method, 
that  of  narcotization,  is  less  often   requisite  ;   the  con- 


MODES    OF    SECURING    ANIMALS 


61 


ditions  under  which  it  is  permissible  will  be  given  in  the 
chapter  on  anaesthetics. 

Frogs  are  fastened  to  a  board,  about  nine  inches  long 
by  three  broad,  by  slip-knots  passed  over  each  elbow  and 
ankle,  Avhile  the  ends  of  the  cords  are  secured  at  the 
corners  of  the  board,  either  by  wrapping  around  cleats, 
or  by  passing  them  through  binding  screws  such  as  are 
ordinarily  used  in  electric  batteries.  Or  holes  may  be 
made  through  the  corners  of  the  board,  and  the  ends 
of  the  cords  passed  through  them,  and  prevented  from 
slipping  either  by  plugging  the  holes  with  small  wooden 
pegs,  or  simply  by  tying  the  ends  of  the  cords  together. 

Rabbits  and  cats  are  best  secured  with  Czermak's 
rabbit-holder  (Fig.  13).     The  bar  h  is  first  passed  be- 

Fiff.  13. 


^^^^^iTTTT 


[F     t^ 


Y 


tt- 


\ 


Czermak's  rabbit-holder. 


hind  the  animal's  incisor  teeth  (the  canines  in  the  case 
of  cats),  the  bar  g  being  below  the  lower  jaw,  and  the 
screw  h  then  tightened  until  the  jaws  are  so  tightly 
compressed  that  the  bar  Ji  cannot  slip  beyond  the  in- 
cisors. The  limbs  are  then  fastened  by  the  slip-knots  at 
w,  and  the  end  of  the  holder  pushed  into  the  fork  at/, 
and  screwed  fast.  The  rabbit  may,  of  course,  be  fast- 
ened either  on  its  back  or  belly,  as  the  conditions  of  the 
experiment  require.  Guinea-pigs  may  be  secured  with 
the  same  apparatus  in  the  same  manner,  it  being,  how- 
ever, generally  necessary  to  pad  the  bars  g  and  g'  with 
6 


62 


GENERAL    ACTION    OF    POISONS. 


Bernard's  dog-holder. 
Fig.  15. 


A.  Improved  form  of  Bernard's  dog-holder.  At  h  is  a  straight  piece  of 
metal  which  passes  beneath  the  dog's  lower  jaw  and  is  connected  with  the 
strap  i,  which  is  fastened  behind  the  head.  The  holder  may  be  moved  back- 
wards or  forwards  by  sliding  the  rod  d  through  the  clamp  e,  or  up  and  down 
by  moving  e  on  the  iron  rod/,  which  is  fastened  to  the  table  by  the  nnt  g. 

B.  Bruntoa's  holder  for  dogs  or  rabbits.  A  loop  of  cord  is  tied  around  the 
upper  jaw,  the  bar  /.  passed  behind  the  canine  teeth  of  the  dog  or  cat,  or  in- 
cisors of  the  rabbit,  and  the  two  jaws  tied  together  to  prevent  its  slipping  out. 
The  fork  fc  is  then  pushed  through  the  holes  in  I,  and  fastened  by  the  screw 
m  ;  k  may  then  be  fastened  to  an  upright  bar  as  in  Czermak's  or  Bernard's 
holders. 


ADMINISTRATION    OF    POISONS.  63 

cotton,  SO  as  to  prevent  them   from   slipping  over   the 
head. 

Dogs  may  be  secured  with  Bernard's  holder  (Fig.  14), 
the  bar  e  being  passed  behind  the  canine  teeth,  and  the 
jaws  fastened  together  by  means  of  a  cord  tied  around 
the  muzzle,  or  the  apparatus  represented  in  Fig.  15 
may  be  used.  The  muzzle  is  passed  through  the  ring, 
and  the  strap  7i,  i  is  tightly  buckled  behind  the  head, 
and  the  screw  e  tightened  up,  so  as  to  prevent  the  jaws 
being  opened,  while  the  strap  prevents  the  head  being 
retracted  ;  the  animal  is  fastened  in  any  desired  position 
by  slip-knots  passed  around  the  legs  and  tied  into  the 
different  holes  in  the  side-boards.  It  is  often  advisable, 
when  very  large  dogs  are  used,  to  pass. the  cords  with 
which  the  forelegs  are  tied  under  the  animal's  body,  and 
then  make  the  ends  fast  on  the  opposite  sides  of  the  box  ; 
by  this  means  the  forelegs  are  held  tightly  against  the 
animal's  sides,  and  the  dog  is  rendered  immovable.  For 
methods  of  fastening  the  larger  mammals  and  birds,  refer- 
ence must  be  made  to  Bernard's  Physiologie  Operatoire, 
or  to  Li  von' s  Manuel  de  Vivisection.~\ 


n. 

ADMINISTRATION  OF  POISONS. 

If  it  is  desired  to  study  only  the  local  effects  of  a 
poison,  no  special  directions  are  required,  it  being  simply 
necessary  to  observe  the  general  rules  that  the  solvent 
employed  must  itself  have  no  irritant  action  on  the  part 
to  which  the  poison  is  applied,  and  that  the  application 
should  be  several  times  repeated  if  the  first  administra- 
tion appear  to  be  without  effect.  As  instances  of  the 
effects  which  might  be  obtained  by  neglect  of  these  pre- 
cautions, we  might  mention  the  fallacy  of  deducing 
results  from  the  application  of  an  alcoholic  solution  to  a 


64  GENERAL    ACTION    OF    POISONS. 

mucous  surface,  the  injection  of  a  fluid  into  the  lungs  to 
determine  the  local  action  on  the  bronchial  mucous  mem- 
brane, or  finally  from  the  single  application  of  tartar 
emetic  to  the  human  skin.  In  nearly  all  cases  control 
experiments  with  the  solvent  alone  should  be  made,  so  as 
to  exclude  the  possibility  of  any  of  the  results  observed 
being  attributable  to  it. 

At  present  we  will  consider  only  the  methods  of  ad- 
ministering drugs  for  the  determination  of  their  gene- 
ral action. 

The  general  action  of  a  poison,  as  will  be  found  later, 
commences  as  soon  as  the  substance  enters  the  circula- 
tion, and  lasts  as  long  as  it  remains  in  the  blood  in  an 
unaltered  condition.  For  the  production,  therefore,  of 
its  general  action,  the  poison  must  be  introduced  in  some 
way  or  other  into  the  blood,  either  in  the  normal  manner 
by  absorption  through  the  closed  walls  of  the  bloodves- 
sels, or  by  being  directly  introduced  into  the  circulation 
through  an  opening  in  the  walls  of  a  vessel. 

Physiological  absorption  always  occurs  gradually  and 
with  varying  degrees  of  rapidity,  depending  upon  the 
locality  of  the  absorbing  surface  and  the  nature  and 
solubility  of  the  poison  ;  while  by  direct  injection  of  the 
substance  into  the  bloodvessels  any  amount  desired  may 
be  allowed  suddenly  to  produce  its  characteristic  action. 

Absorption  occurs  most  slowly  when  the  drug  is  brought 
into  contact  only  with  the  external  skin ;  more  rapidly 
with  mucous  surfaces  and  the  internal  surfaces  of  serous 
sacs,  such  as  the  lymph-sacs  beneath  the  skin  of  the  frog  ; 
and  with  still  greater  rapidity  when  brought  in  contact 
with  wounds  in  the  skin  or  mucous  surfaces,  or  when  in- 
troduced into  the  subcutaneous  connective  tissue  (hypo- 
dermic injection).  These  last  three  methods  have  the 
point  in  common  that  by  the  anatomical  lesion  the  sub- 
stance is  brought  into  direct  contact  with  the  walls  of 
the  capillaries,  and  possibly  with  openings  in  their  walls, 
while  in  the  other  methods  the  substance  is  separated 
from  the  bloodvessels  by  an  epithelial  layer  which  is 
only    traversed    with    comparative    difficulty.      By    the 


INJECTION  INTO  THE  BLOODVESSELS.     65 

selection  of  one  of  these  methods,  therefore,  it  is  possible 
to  regulate  the  rate  of  action  of  the  poison,  and  obtain 
any  varying  degree  of  rapidity  from  the  instantaneous 
action  of  substances  injected  directly  into  the  vessels,  to 
the  extremely  slow  and  gradual  action  when  the  poison 
is  brought  in  contact  with  the  external  skin.  It  must, 
however,  be  emphasized  that  not  only  the  rapidity  of 
appearance  of  the  general  action  but  also  the  existence 
of  any  general  action  may  depend  upon  the  mode  of 
administration.  It  will  be  shown  later,  that  the  general 
action  of  every  poison  depends  upon  the  presence  of  a 
certain  amount  of  that  substance  in  the  blood,  and  that 
the  amount  circulating  in  the  blood  depends  not  only  on 
the  amount  administered  but  upon  the  rapidity  with  which 
excretion  takes  place  ;  and  it  can  accordingly  happen  that 
a  poison  which  in  itself  is  very  active  may  from  slow 
absorption  and  rapid  excretion  not  attain  a  sufficient 
amount  at  any  one  time  in  the  blood  to  produce  any 
effect. 

Since,  then,  by  the  choice  of  the  mode  of  administra- 
tion we  can  accelerate,  hinder,  or  prevent  the  production 
of  the  general  action  of  a  poison,  and  since  the  rapidity 
with  which  the  symptoms  appear  has  a  marked  influence 
on  the  general  picture  of  the  poisoning,  and  since  many 
poisons  may  be  chemically  altered  by  the  peculiarities  of 
the  absorbing  surfaces,  it  is  advisable  to  perform  a  num- 
ber of  experiments  in  which  these  different  methods  of 
administration  are  employed. 


Section  I. — Injection  into  the  Bloodvessels. 

In  the  case  of  many  poisons  the  action  will  differ, 
depending  upon  whether  it  is  injected  into  an  artery  or 
a  vein.  As  a  general  rule  it  is  preferable  to  inject  the 
drug  into  a  vein  ;  in  the  first  place,  on  account  of  the 
readiness  with  which  large  veins,  from  their  superficial 
location,  can  be  isolated  ;  second,  on  account  of  the  sen- 
sibility of  arteries  ;  and  third,  and  most  important  of  all, 

6* 


6Q  GENERAL    ACTION    OF    POISONS. 

because  substances  injected  into  a  vein  are  first  carried 
to  the  heart  and  then  gradually  carried  to  all  parts  of 
the  system.  Injections  into  the  venous  system  are  most 
easily  made  in  mammals  into  the  external  jugular  vein, 
and  preferably  towards  the  heart,  since  in  this  direction 
larger  quantities  of  fluid  can  be  thrown  into  the  circu- 
lation than  when  it  is  injected  towards  the  periphery 
where  the  resistance  of  the  valves  and  of  the  capillaries 
may  easily  prevent  the  entrance  of  fluid.  In  the  frog, 
only  the  large  venous  trunks  are  suitable  for  injections. 

In  all  injections,  especially  when  made  into  the  cen- 
tral end  of  the  jugular  vein,  the  entrance  of  air  must  be 
avoided  with  the  greatest  care. 

The  external  jugular  vein  is  exposed  in  the  following 
manner :  After  cutting  the  hair  from  the  parts,  a  short 
incision  is  made  through  the  skin  of  the  neck  in  a  line 
drawn  from  the  angle  of  the  jaw  to  the  jugular  notch 
in  the  sternum;  then,  on  carefully  clearing  away  the 
fat  and  connective  tissue  with  two  pairs  of  forceps,  or 
with  a  blunt  hook,  the  dark  blue  vein,  usually  sending 
off  numerous  branches,  is  exposed  to  view.  The  vein  is 
then  to  be  carefully  freed  from  its  connective-tissue 
sheath  for  a  length  of  about  2  cm.,  and  a  double  thread 
passed  beneath  it  with  a  curved,  blunt  needle  ;  the  cen- 
tral end  of  the  isolated  portion  is  then  to  be  compressed 
with  a  spring- clip,  or  with  a  loop  tied  in  a  single  bow- 
knot,  and  the  peripheral  end  ligated  with  one  of  the 
threads  previously  passed  around  the  vein.  The  portion 
of  the  vein  lying  between  the  ligature  and  the  clip  (or 
loop),  which,  from  the  order  of  applying  the  ligatures,  is 
distended  with  blood,  is  then  snipped  with  a  pair  of  scis- 
sors cutting  well  at  the  points,  and  a  glass  or  metal  canula 
inserted  and  tied  in  by  the  remaining  thread. 

The  canula  can  be  conveniently  furnished  with  a  stop- 
cock, and,  before  insertion,  must  be  completely  filled 
with  distilled  water,  which  is  prevented  from  flowing  out 
by  closing  the  cock.  After  the  insertion  of  the  canula, 
the  spring-clip  on  the  vein  can  be  removed.  The  poison 
is  to  be  injected  by  means  of  a  metal  or  glass  syringe. 


INJECTION  INTO  THE  BLOODVESSELS.     67 

conveniently  graduated  into  cubic  centimeters,  whose 
nozzle  must  accurately  fit  the  moutli  of  the  canula.  [If 
a  glass  canula  is  used,  it  is  only  necessary  that  the  free 
end  be  inserted  into  a  piece  of  rubber  tube,  about  an 
inch  long,  which  fits  the  end  of  the  syringe.  It  is  then 
not  necessary  to  fill  the  canula  until  it  is  desired  to  make 
the  injection,  when  it  is  advisable  to  fill  the  canula  com- 
pletely with  the  solution  to  be  injected,  instead  of  water  ; 
of  course,  then,  the  clip  must  not  be  removed  from  the 
vein  until  after  the  syringe  is  bound  into  the  rubber 
end  of  the  canula.] 

The  injection  must  be  made  slowly  and  gradually,  and 
care  must  be  taken,  by  holding  the  canula,  that  the  syringe 
does  not  separate  from  the  canula  by  the  force  necessary 
in  making  the  injection  ;  it  is,  therefore,  an  advantage 
to  use  a  syringe  on  the  upper  end  of  which  are  two  rings 
for  the  insertion  of  the  second  and  third  fingers,  while 
the  thumb  is  passed  into  a  ring  in  the  end  of  the  piston- 
rod,  so  as  to  admit  of  one  hand  manipulating  the  syringe, 
while  the  other  holds  the  canula.  When  it  is  desirable 
to  inject  the  poison  into  the  arterial  system,  the  carotid 
or  femoral  artery  is  selected,  unless  there  is  some  special 
reason  for  the  use  of  other  vessels.  The  carotid  artery 
is  exposed  by  an  incision  parallel  to  the  trachea,  passing 
between  the  sterno-hyoid  and  sterno-mastoid  muscles; 
it  lies  in  the  common  sheath  with  the  vagus,  sympa- 
thetic, etc.  The  crural  artery  is  readily  found  in  the 
inner  aspect  of  the  thigh,  below  Poupart's  ligament, 
where  it  lies  very  superficially  and  may  be  felt  through 
the  skin. 

Canulge  similar  to  those  employed  in  the  veins  may 
also  be  used  for  arterial  injections,  either  toward  the 
heart  or  the  periphery  ;  in  both  cases  considerable  re- 
sistance is  met  with,  from  the  general  arterial  tension  in 
the  first  case,  and  from  the  capillary  resistance  in  the 
second.  Injections  towards  the  periphery  invariably 
evoke  the  symptoms  due  to  the  poison  first  in  the  organs 
supplied  by  the  artery,  while  when  injected  toward  the 
heart,  this  is  the  organ  first  affected,  and  then  the  entire 


68  GENERAL    ACTION    OF    POISONS. 

system  is  gradually  brought  under  its  influence.  This 
latter  method  is  to  be  preferred  unless  some  local  effect 
is  to  be  studied,  though  it  should  be  remembered  that  a 
marked  accelerative  eff'ect  on  the  heart  can  be  thereby 
produced.  Canulae  are  inserted  into  arteries  in  precisely 
the  same  manner  as  into  the  veins. 

Injections  into  arteries  have  the  disadvantage  that  in 
most  cases  they  are  extremely  painful,  and  that  the  evi- 
dences of  pain  on  the  part  of  the  animal  may  be  con- 
founded with,  or  mask,  the  specific  effects  of  the  drug. 
In  such  cases,  therefore,  if  possible,  a  control  experi- 
ment must  be  made  after  the  narcotization  of  the  animal. 

It  cannot  be  too  much  emphasized  that  by  no  means 
all  poisons  are  suited  for  direct  injection  into  the  circu- 
lation. It  is  evident  that  solid  particles,  even  if  sus- 
pended in  a  fluid,  cannot  be  injected  into  the  blood,  since 
they  would  remain  as  emboli  at  the  narrower  subdivisions 
of  the  vessels.  Nor,  again,  can  fluids  be  injected  which 
produce  emboli  by  causing  a  precipitate  in  the  blood. 
It  would,  for  example,  be  an  extremely  defective  experi- 
ment to  inject  a  mineral  acid  into  the  blood,  since  the 
coagula  thereby  produced  would  be  swept  into  the  cir- 
culation, form  emboli,  and  produce  symptoms  which 
would  in  no  way  depend  upon  the  specific  action  of  the 
substance  injected. 

It  must,  therefore,  not  be  forgotten  that  the  object  of 
the  injection  of  a  poison  into  the  blood  is  not  to  deter- 
mine the  action  of  the  poison  on  the  blood,  but  only  to 
evoke,  in  the  most  rapid  manner,  the  general  symptoms 
due  to  the  poison,  after  having  first  excluded  by  experi- 
ment every  possible  alteration  of  the  drug  before  absorp- 
tion occurs ;  therefore,  an  injection  should  never  be 
made  into  the  circulation  until  it  is  known  what  changes, 
if  any,  occur  either  in  the  blood  or  drug  when  the  two 
are  brought  in  contact  (see  p.  20). 

On  the  other  hand,  even  when  it  has  been  found  that 
the  poison  causes  a  precipitate  when  mixed  with  the 
blood,  it  may  be  necessary,  in  exceptional  cases,  to  inject 
that  poison  into  the  blood  to  settle  the  question  as  to 


INJECTION    INTO    THE    BLOODVESSELS.  69 

whether  the  general  toxic  effects  of  the  substance  other- 
wise administered  are  due  to  the  production  of  emboli. 

Aeriform  poisons  are  also  unsuitable  for  intravascular 
injections,  although  pharmacological  literature  is  rich  in 
such  experiments.  In  the  first  place,  the  entrance  of 
any  gas,  even  should  it  be  considered  most  absorbable, 
into  a  bloodvessel,  by  producing  gaseous  emboli,  can 
evoke  the  same  symptoms  as  follow  the  entrance  of  air 
into  the  veins.  In  the  second  place,  there  can  be  nothing 
gained  by  injecting  a  gas  into  a  bloodvessel,  even  if 
this  danger  could  be  avoided  ;  since  a  gas  cannot  possibly 
enter  the  blood  more  rapidly  than  by  absorption  through 
the  lungs,  where  a  much  larger  surface  of  blood  is  ex- 
posed to  its  influence  than  when  it  is  injected  into  a  ves- 
sel. For  example,  it  is  not  possible  to  inject  oxygen 
into  a  vein  in  sufficient  quantity  and  rapidity  to  prevent 
the  appearance  of  dyspnoea,  if  other  sources  of  oxygen 
are  withheld.  Here,  however,  as  in  the  fir^t  instance  of 
unsuitable  injections,  exceptional  circumstances  may  ren- 
der the  administration  of  gases  through  the  lungs  impos- 
sible, as  when  it  is  desired  to  determine  whether  the 
poison  is  eliminated  through  the  lungs  ;  even  in  such  a 
case,  however,  the  subcutaneous  injection  of  the  gas  is 
preferable  to  its  direct  introduction  into  a  vein. 

If  the  gas  is  readily  soluble  in  water,  there  is  no 
objection  to  the  injection  of  an  aqueous  solution  into  a 
bloodvessel,  or  a  quantity  of  blood  may  be  drawn  from 
the  animal,  defibrinated,  treated  with  the  gas,  and  again 
injected  after  being  warmed  up  to  the  body  temperature. 
For  sucli  an  experiment  it  may  be  advantageous  to  make 
use  of  a  T- formed  canula,  so  that  the  blood  may  be  drawn 
from  one  end  of  the  vessel  and  injected  into  the  other. 
A  simple  canula,  fastened  into  the  central  end  of  a  vein, 
will,  however,  answer  every  purpose,  as  sufficient  blood 
can  be  drawn  from  the  vessel  by  a  syringe  inserted  into 
the  canula. 


70  GENERAL    ACTION    OF    POISONS. 


Section  II. — Subcutaneous  Injections  and  Injections 
into  Serous  Sacs,  Lymph  Sacs  of  the  Frog,  etc. 

Graduated  syringes,  such  as  employed  in  injections 
into  veins,  may  be  used,  substituting  for  the  canulae  then 
used,  the  ordinary  hypodermic  needles,  or  tubes  with 
sharpened  points  ;  after  the  injection  has  been  made  by 
pinching  up  a  fold  of  skin  and  inserting  the  needle  nearly 
horizontally,  the  needle  and  syringe  are  withdrawn  to- 
gether, and  the  wound  of  entrance  of  the  needle  closed  for 
a  few  seconds  with  the  finger  to  prevent  the  escape  of  the 
fluid  ;  it  is  also  advantageous  to  draw  the  skin,  before  the 
injection,  to  one  side,  so  that,  the  wounds  in  the  skin  and 
connective  tissue  not  coinciding  when  the  skin  regains  its 
natural  position,  a  valvular  opening  is  made  and  the 
escape  of  fluid  further  prevented. 

[In  frogs  the  solution  may  be  injected  into  the  abdomi- 
nal cavity  or  under  the  skin  of  the  back,  when  it  will 
find  entrance  into  the  large  dorsal  lymph-sac,  and  thence 
be  rapidly  carried  into  the  general  circulation.  In 
rabbits,  guinea-pigs,  and  dogs,  it  may  be  injected  under 
the  skin  of  the  flank,  though  it  is  only  convenience  in 
handling  which  renders  this  locality  to  be  preferred  to 
any  other ;  in  guinea-pigs  the  abdominal  walls  are  ex- 
tremely thin,  so,  if  this  situation  be  used,  care  must  be 
taken,  when  comparative  experiments  are  made,  that  the 
abdominal  cavity  is  not  penetrated  by  the  needle,  when, 
of  course,  absorption  would  be  much  more  rapid.] 


Section  III.— Insertion  of  Poisons  into  the  Mucous 
Cavities  of  the  Body. 

In  many  cases,  poisons  may  be  introduced  into  the 
stomach  of  animals  by  mixing  them  with  the  food ; 
usually,  however,  it  is  better  to  inject  them,  especially 
when  fluid,  by  means  of  a  stomach  tube.  In  rabbits,  an 
ordinary  medium-sized  flexible  catheter  will  answer  this 


INSERTION   OF  POISONS  IN    MUCOUS   CAVITIES.      71 

purpose  ;  for  its  introduction  the  animal  is  held  with  the 
head  well  extended  and  the  jaws  tightly  closed,  so  that 
it  cannot  bite  the  catheter,  which,  after  being  well  oiled, 
is  passed  into  the  mouth  behind  the  incisor  teeth  and 
pushed  well  backward,  when  ordinarily  it  will  pass  with- 
out difficulty  into  the  oesophagus.  If  it  should  pass  into 
the  trachea,  as  would  be  rendered  evident  by  the  resist- 
ance of  the  vocal  cords  and  the  occurrence  of  dyspnoea 
on  closing  the  catheter,  it  must  be  withdrawn  and  re- 
inserted. The  end  of  the  catheter  must  be  furnished 
with  a  short  piece  of  rubber  tubing  which  will  fit  the 
nozzle  or  canula  of  the  syringe,  and  the  syringe  and  cathe- 
ter must  be  withdrawn  together  after  making  the  injection 
[otherwise,  the  catheter  remaining  alone  would  act  like 
a  siphon  and  allow  the  contents  of  the  stomach  to  escape]. 
Qlisophageal  sounds,  similar  to  those  employed  in  man, 
can  readily  be  introduced  in  dogs  over  a  block  of  wood 
so  inserted  as  to  keep  their  jaws  wide  apart: — this  block 
may  conveniently  have  a  hole  bored  in  its  centre  for  the 
passage  of  the  sound,  and  two  straps  at  its  ends  to  buckle 
behind  the  head  and  so  keep  it  in  position.  A  similar 
operation  is  readily  performed  on  cats,  making  use  of  a 
smaller  wooden  or  iron  bar  to  keep  the  jaws  open. 

In  frogs,  after  opening  the  mouth  with  the  handle  of 
a  scalpel,  an  ordinary  canula  can  be  passed  into  the 
stomach,  and  the  injection  made  through  it.  Solid  bodies, 
such  as  crystals,  can  be  readily  pushed  into  the  stomach 
by  means  of  a  glass  rod. 

Applications  to  the  rectum,  bladder,  etc.,  are  per- 
formed in  the  ordinary  well-known  manner.  Instillations 
into  the  conjunctival  sac  are  best  made  by  drawing  the 
lower  eyelid  away  from  the  eyeball  with  the  hand  or  a 
pair  of  forceps,  and  then  dropping  the  solution  by  means 
of  a  pipette,  or  medicine-dropper,  into  the  open  sac  ;  it 
is  well  to  maintain  this  everted  position  of  the  lower 
eyelid  for  some  little  time,  so  as  to  permit  of  absorp- 
tion before  much  of  the  fluid  is  lost  by  closure  of  the 
eyelids.  This  method  is  only  suitable  for  studying  the 
local  action  of  the  poison. 


72  GENERAL    ACTION    OF    POISONS. 

The  bronchial  mucous  membrane  is  almost  never  to 
be  used  for  the  absorption  of  solutions.  Should  it, 
however,  be  necessary  to  make  the  experiment,  a  canula 
can  be  readily  introduced  into  the  windpipe  by  perform- 
ing tracheotomy,  and  the  poison  injected.  A  great  deal 
of  force  will  be  required  to  inject  the  solution  into  the 
bronchioles. 


Section  IV. — Administration  of  Gases  and  Vapors 
through  the  Lungs. 

This  method  of  administration  of  poisons  is  very  often 
desirable,  and  can  be  accomplished  in  several  difterent 
ways,  depending  upon  whether  the  gas  may  be  mingled 
with  the  inspired  air  or  must  be  separated  from  it. 

Small  animals,  such  as  frogs,  birds,  and  the  smaller 
mammals,  may  be  placed  in  a  chamber  filled  with  the 
gas  either  before  or  after  the  introduction  of  the  animal. 
In  the  first  case,  when  frogs  are  employed,  it  is  only 
necessary  to  float  a  bell-jar  containing  the  gas  on  water 
or  mercury,  and  then  pass  the  animal  through  the  water 
into  the  holder ;  this  method  may  also  be  employed  for 
other  animals,  but  it  has  the  disadvantage  of  chilling  the 
animal  from  the  necessary  wetting  ;  on  the  other  hand,  it 
has  the  advantage  of  plunging  the  animal  suddenly  into  an 
atmosphere  of  the  gas  whose  effects  it  is  desired  to  study  ; 
the  air  contained  in  the  animal's  lungs,  particularly  in 
the  case  of  frogs,  may  be  largely  expelled  by  pressure 
under  the  water. 

The  other  method  consists  in  placing  the  animal  under 
a  bell-jar,  or  in  a  cylinder,  through  the  top  of  which  the 
gas  is  passed  by  means  of  a  tube  reaching  to  the  bottom 
of  the  vessel,  while  the  air  is  allowed  to  escape  through 
a  second  opening  in  the  top.  In  order  to  regulate  the 
entrance  of  the  gas,  the  bottom  of  the  receiver  may  be 
covered  with  a  layer  of  water,  under  which  the  tube  of 
entrance  dips,  so  that  the  rate  of  entrance  may  be  known 
by  the  rapidity  with  which  the  gas-bubbles  pass,  while 


ADMINISTRATION  OF  GASES  BY  THE  LUNGS.   73 

the  animal  may  be  placed  on  a  board  which  either  floats 
on  the  surface  of  the  water  or  is  raised  above  it  by  sup- 
ports. This  method  is,  however,  only  applicable  when 
complete  exclusion  of  atmospheric  air  is  not  essential. 

In  most  cases  it  is  much  more  advantageous  to  con- 
nect the  animal's  lungs  directly  with  the  gas  apparatus. 
To  accomplish  this,  it  is  not  always  necessary  to  perform 
tracheotomy,  as  the  head  may  be  covered  with  a  rubber  bag 
or  cap  which  is  in  communication  with  the  gas  receiver. 
In  rabbits,  when  it  is  desired  to  avoid  tracheotomy,  the 
head  can  be  passed  into  a  funnel,  fastened  by  appropriate 
bands,  while  the  space  between  the  neck  and  the  funnel 
can  be  plugged  almost  air  tight  with  cotton  or  wool. 

For  experiments  on  man,  it  is  only  necessary  to  insert 
a  tube,  through  which  the  gas  is  conducted,  into  the 
mouth,  while  the  nostrils  are  closed. 

As  a  rule,  it  is  preferable  to  perform  tracheotomy  on 
animals,  since  then  the  exclusion  of  air  is  assured  and 
influence  on  the  glottis  is  avoided,  thus  rendering  ex- 
periments with  irrespirable  gases  possible.  Tracheal 
canulae,  of  the  same  shape  as  the  venous  canulae,  but  of 
larger  size,  can  be  employed,  though  f-shaped  glass  or 
brass  tubes  are  better. 

Modifications  of  this  method  will  be  necessary  if  it  is 
desired  to  separate  the  air  of  inspiration  from  that  of 
expiration.  In  any  case,  however,  it  is  only  permissible 
to  allow  the  animal  continuously  to  inspire  and  expire 
into  a  closed  gas-chamber,  when  the  vessel  is  so  large  or 
the  duration  of  the  experiment  so  short,  that  the  increas- 
ing contamination  of  the  gas  from  the  products  of  expira- 
tion and  absence  of  oxygen  is  not  to  be  feared.  If  the 
gas-holder  is  so  large  in  comparison  to  the  thorax  of  the 
animal  that  the  variations  of  pressure  on  inspiration  and 
expiration  are  very  small,  and  it  is  not  necessary  that 
the  volume  of  the  holder  should  change  with  the  phases 
of  respiration,  a  simple  gasometer  or  even  a  large  bell-jar 
floating  in  water  with  an  opening  connecting  with  the  tra- 
cheal tube  will  answer.  As  a  rule,  however,  the  gas- 
holder should  readily  decrease  in  volume  in  inspiration 


74  GENERAL    ACTION    OF    POISONS. 

and  increase  in  expiration ;  such  gasometers  may  be 
represented  by  rubber  or  silk  bags,  or  by  a  Hutchinson's 
spirometer  when  the  air-chamber  is  accurately  balanced 
and  care  taken  to  expel  all  the  air  from  its  interior. 

In  the  most  careful  experiments  the  inspired  air  should 
be  separated  from  that  expired.  For  this  purpose  the 
tracheal  canula,  or  the  tube  of  the  funnel  used  as  a  mask, 
must  be  connected  with  a  fork-shaped  tube,  of  which  one 
prong  must  be  furnished  with  a  valve  opening  only 
towards  the  interior,  the  other  with  a  valve  opening  only 
towards  the  exterior.  For  this  purpose,  there  is  nothing 
better  than  Miiller's  liquid  valves  which  are  perfectly 
efficacious  in  forming  tight  joints  and  which  can  be 
readily  prepared.^  These  consist  of  bottles  (with  one 
or  two  necks)  through  the  corks  of  which  two  tubes  are 
passed,  one  passing  merely  through  the  cork,  the  other 
to  the  bottom  of  the  flask,  and  dipping  below  a  layer  of 
liquid,  either  water  or  mercury.  Gases  can  then  only  be 
passed  through  the  flasks  from  the  longer  to  the  shorter 
tube,  provided  that  the  pressure  is  not  sufficient  to  raise 
a  column  of  the  liquid  used  higher  than  the  length  of  the 
lonorer  tube.  Two  of  these  flasks  are  then  so  arranored 
that  the  inspiration  flask  has  its  shorter  tube,  and  the 
expiration  flask  has  its  longer  tube,  connected  with  the 
forked-shape  tube  of  the  tracheal  canula :  the  length  of 
the  long  tube  must  be  proportionate  to  the  strength  of 
respiration  in  the  animal,  and  when  mercury  is  used  as  a 
valve  it  can  naturally  be  much  shorter  than  when  Avater 
is  used  for  the  same  purpose ;  hence  when  dogs  are 
used  and  where  quantitative  analyses  of  the  expired  gases 
are  made,  particularly  of  such  gases  as  carbonic  acid, 
which  is  soluble  in  water,  it  is  always  advisable  to  era- 
ploy  mercury. 

The  long  tube  of  the  inspiratory  valve  is  then  con- 
nected with  the  gas-holder,  for  which  either  a  spirome- 
ter, or  Rosenthal's  modification  of  Bunsen's  gasometer, 
when  it  is  desired  to  shut  ofl"  the  gas-supply  through  mer- 

'  Annalen  der  Chemie  uiid  Pharin.,  cviii.  257. 


ADMINISTRATrON    OF    GASES    BY    THE    LUNGS.       75 

cury,  may  be  used.*  The  short  arm  of  the  expiratory 
valve  either  opens  into  the  air  or  into  a  gas-holder  when 
it  is  desired  to  examine  the  expired  air. 

If  it  is  desired  to  mix  small  quantities  of  the  poisonous 
gas  with  the  atmosphere  before  inspiration,  the  long  tube 
of  the  inspiratory  valve  may  communicate  with  the  atmo- 
sphere, and  a  second  long  tube  in  the  same  flask  may  be 
connected  with  a  gas-holder  or  bag.^ 

If  experiments  are  being  made  with  a  gas  which  is 
freely  soluble  in  water,  or  with  the  vapor  of  volatile 
liquids,  the  solution  of  gas  in  water  or  the  volatile  liquid 
may  replace  the  fluid  which  acts  as  a  valve  in  the  inspi- 
ratory flask,  which,  if  necessary,  may  be  warmed  to 
facilitate  its  vaporization.  So,  also,  the  fluid  in  the 
expiratory  flask  may  be  replaced  by,  or  covered  by,  a 
layer  of  reagents,  which,  by  their  chemical  behavior, 
will  show  the  presence  of  certain  substances  in  the 
expired  air. 

In  all  experiments  in  which  respiration  is  carried  on 
by  the  animal,  the  tubes  in  these  valves  should  be  wide, 
and  not  too  long,  so  as  not  to  cause  dyspnoea  from 
resistance  to  respiration.  In  many  cases,  it  is  prefer- 
able to  force  the  gases  into  the  animal's  lungs,  rather 
than  to  depend  upon  its  own  respiratory  powers,  thus 
rendering  it  possible  to  open  the  thorax  and  inspect  the 
heart,  and  to  study  the  action  of  the  gas  after  the  pro- 
duction of  apnoea.  The  principal  difficulty  met  with  in 
accomplishing  this  lies  in  the  production  of  expiration. 
Hook's  method  was  to  neglect  expiration  entirely,  and 
to  pass  the  gas  continually  through  the  lungs  by  open- 
ing the  thorax,  and  then  incising  the  lungs  in  several 
places ;  apart  from  the  loss  of  blood  entailed  by  this 
proceeding,  it  has  the  further  disadvantage,  that,  even 
when  numerous  openings  are  made  in  the  lungs,  the 
entire  organ  is  not  permeated  by  the  gas,  since  many 
portions  collapse. 

1  Rosenthal,  Arch.  f.  Anat.  u.  Phys.,  1864,  456. 
*  Kaufmann  u.  Rosenthal,  ditto,  1865,  659. 


76  GENERAL    ACTION    OF    POISONS. 

Passive  or  active  expiration  can  be  produced  in  unin- 
jured lungs  in  one  of  two  ways:  in  the  first,  the  tra- 
cheal canula  has  an  opening  at  one  side,  through  which 
the  lungs,  by  contracting  from  their  own  elasticity,  are 
enabled  to  force  out  the  expired  air  during  the  pauses 
between  inspirations  ;  this  opening,  by  graduation  of  its 
size,  has  the  further  function  of  acting  as  a  safety  valve, 
and  preventing  rupture  of  the  lungs  by  too  great  a  pres- 
sure in  inspiration.  This  opening  can  also  be,  with  ad- 
vantage, connected  with  a  Miiller's  valve,  and  the  resist- 
ance can  then  be  regulated  at  pleasure.  When  extremely 
poisonous  gases  are  being  experimented  with,  this  open- 
ing, or  the  short  tube  of  the  valve,  should  be  connected 
with  a  tube  by  which  the  expired  air  may  be  conducted 
out  of  the  laboratory. 

The  other  method  consists  in  interposing  between  the 
lungs  and  the  gas-apparatus  a  two-way  cock  which  works, 
by  some  mechanism,  in  the  rhythm  of  respiration.  For 
this  purpose  the  fork-shaped  tube  may  be  connected 
with  two  rubber  tubes  which  are  alternately  compressed 
by  a  lever. ^ 

For  the  production  of  artificial  respiration,  any  of  the 
various  forms  of  blast  apparatus,  described  in  all  hand- 
books for  the  laboratory,  may  be  made  use  of.  When  a 
constant  force  only  is  required,  the  gas  may  be  passed 
directly  from  the  generator ;  but  where  a  rhythm  is 
required  for  forcing  atmospheric  air,  an  ordinary  bellows 
worked  by  hand,  gas,  or  water-power,  will  answer  every 
purpose.2  When  bellows  are  used  to  force  gas  other 
than  air  into  the  lungs,  the  entrance  valve  of  the  bellows 
must  be  connected  with  the  gas-holder,  while  the  nozzle 
of  the  bellows  communicates  with  the  lungs.  Various  other 
arrangements  for  producing  a  constant  or  rhythmical 
air  blast  will  readily  suggest  themselves  if  the  above  are 
not  accessible ;  such  as  an  ordinary  rubber  bulb  arranged 

1  Rosenthal,  Arch.  f.  Anat.  u.  Phjs.,  1864,  456. 

2  Thiry  describes  a  simple  form  of  automatic  respiration  appa- 
ratus in  Recueil  des  Travaux  de  la  Soc.  Med.  AUemande,  Paris, 
18.55,  55. 


ELIMINATION    AND    CHANGES    OF    POISONS.      77 

with  valves  actin<^  in  the  same  direction,  and  compressed 
rhythmically  under  the  foot. 

One  other  arrangement  is  necessary  to  complete  the 
apparatus  for  the  study  of  poisons  administered  through 
the  lungs.  In  order  to  obtain  an  uncomplicated  result 
from  the  action  of  any  poisonous  gas  or  vapor,  it  is  neces- 
sary that  it  should  be  suddenly  substituted  for  the 
atmospheric  air ;  if  the  animal  is  breathing  sponta- 
neously, it  suffices  to  suddenly  connect  the  tracheal 
canula  with  the  inspiratory  valves  connected  with  the 
gas-holder,  as  can  be  readily  done  with  a  three-way  cock, 
one  opening  of  which  communicates  with  the  atmosphere. 
In  artifical  respiration  the  three-way  cock  can  be  inserted 
between  the  blast  and  the  gas-holder,  an  arrangement 
which  will  permit  the  introduction  of  the  gas  after  the 
production  of  apnoea  by  forced  inspiration. 

Other  modes  of  application  do  not  require  any  special 
mention. 


III. 

INVESTIGATION  OP  THE  PATHS  OF  ELIMINATION  AND 
CHANGES  OF  POISONS  IN  THE  BODY. 

From  the  great  diversity  of  poisons,  only  a  few  gene- 
ral rules  can  be  given  for  the  elucidation  of  these  points ; 
as  a  rule,  the  most  various  chemical  manipulations  are 
requisite.  It  has  been  already  said  that  the  general 
action  of  a  poison  can  only  appear  after  its  entrance 
into  the  blood,  and  since  many  poisons,  for  which  there 
are  no  known  chemical  tests,  produce  marked  symptoms 
in  extremely  minute  quantities,  the  appearance  of  the 
characteristic  effects  is  in  most  cases  a  far  more  delicate 
test  of  the  presence  of  the  poison  in  the  blood  than  can 
be  obtained  by  any  chemical  reagent.  Nevertheless  the 
appearance  of  certain  symptoms  after  the  administration 
of  a  poison    does    not  exclude  the  possibility  of  some 


78  GENERAL    ACTION    OF    POISONS. 

change  in  the  constitution  of  that  poison  after  absorption, 
as  the  products  of  decomposition  of  the  poison  may 
themselves  have  been  the  cause  of  the  symptoms  ;  there- 
fore it  is  advisable  to  attempt  the  recognition  by  chemi- 
cal means,  difficult  though  it  be,  of  the  presence  of  the 
drug  in  the  blood.  In  all  cases,  particularly  where 
organic  poisons  are  concerned,  the  blood  should  be  ex- 
amined as  soon  as  possible  after  withdrawal  from  the 
body  ;  in  many  cases  when  the  recognition  of  the  poison 
in  the  blood  fails,  the  poison  can  be  detected  unaltered 
in  the  secretions,  such  as  the  saliva  or  urine. 

The  greatest  diversity  may  exist  as  to  the  ultimate 
fate  of  a  poisonous  substance  introduced  into  the  blood  ; 
and  this  diversity  will  be  more  marked  the  more  rapidly 
death  puts  an  end  to  the  tissue  changes. 


Section  I. — Passage  of  Drugs  through  the  System 
without  Change. 

The  usual  fate  of  foreign  substances  introduced  into 
the  organism  is  that  they  sooner  or  later,  in  different 
manners,  are  excreted  from  the  body,  while  their  extended 
or  permanent  deposit  in  the  tissues  is  exceptional. 

There  are  two  organs  which  especially  have  for  their 
function  the  removal  of  deleterious  substances  from  the 
blood  ;  the  kidneys  for  fluids  or  solutions,  the  lungs  for 
gases  and  vapors.  In  the  former,  the  blood  loses  large 
quantities  of  fluid,  which,  from  the  laws  of  diffusion,  must 
carry  with  it  appreciable  quantities  of  the  substances  in 
solution  in  the  serum.  In  the  latter,  at  least  during 
respiration,  large  blood  surfaces  are  in  contact  with  the 
atmosphere,  and  since  this  atmosphere  at  best  can  contain 
but  traces  of  the  deleterious  gaseous  substances  in  the 
blood,  and  therefore  under  less  tension  than  in  the  blood, 
they  tend  to  constantly  diftuse,  under  ordinary  physical 
laws,  from  the  blood  into  the  air  in  the  lungs.  Ex- 
ceptional circumstances  may,  however,  occur  in  which 
these  physical  processes  will  be  either  hindered  or  facili- 


PASSAGE    OF    DRUGS    THROUGH    THE    SYSTEM.       79 

tated.  For  example,  diiFusion  will  be  prevented  by 
chemical  union  of  the  foreign  bodies  with  the  ingredients 
of  the  blood,  or  accelerated  by  chemical  forces  tending  to 
displace  them  from  the  blood.  As  an  illustration  of  the 
former  condition,  carbon  monoxide  may  be  mentioned, 
which,  from  its  chemical  relations  with  the  blood,  shows 
no  tendency  to  diffuse  into  the  air  in  the  lungs  ;  while  as 
an  example  jof  the  second,  carbon  dioxide,  though  form- 
ing a  chemical  compound  with  the  blood,  is  diffused  with 
the  greatest  readiness.  Similar  conditions  exist  as  re- 
gards the  elimination  of  substances  through  the  kidney. 

As  in  the  kidneys,  so  also  in  all  the  other  emunctory 
organs,  there  is,  probably,  a  tendency  to  the  elimination 
of  foreign  substances  from  the  blood ;  therefore  drugs, 
after  absorption,  may  appear  in  the  saliva,  in  mucus,  the 
gastric,  intestinal  or  pancreatic  juices,  or  in  bile,  in  the 
digestive  apparatus ;  or  in  the  sweat,  milk,  tears,  or  lymph 
juices.  Of  these  secretions,  the  milk,  sweat,  or  saliva  can 
serve  to  eliminate  the  poison  entirely  from  the  system  ; 
the  others  can  remove  it  only  temporarily  from  the  blood 
to  place  it  under  circumstances  where  it  again  meets  condi- 
tions favorable  for  reabsorption  into  the  blood  by  the 
vascular  or  lymphatic  vessels.  The  laws  which  govern 
this  intermediate  circulation  of  poisons,  as  of  the  normal 
results  of  tissue  change,  are  almost  entirely  unknown. 

So  far  as  the  mere  phenomena  of  diffusion  are  concerned, 
substances  with  low  osmotic  equivalents,  such  as  soluble 
salts,  will  naturally  tend  to  follow  the  path  of  the  water 
in  the  organism,  and  hence  first  tend  to  appear  in  the 
fluid  excretions,  especially  in  the  urine,  where  many  of 
these  bodies,  such  as  iodide  and  ferrocyanide  of  potas- 
sium, are  readily  and  rapidly  detected  after  their  entrance 
into  the  circulation.  The  rapidity  of  this  excretion,  as 
already  suggested  (page  65),  can  explain  the  non-appear- 
ance of  symptom.s  of  poisoning  after  the  administration 
of  the  poison  by  the  stomach,  since  the  rapid  removal  by 
excretion  of  the  substance  from  the  blood  prevents  its 
accumulation  in  sufficient  quantity  to  produce  any  evi- 
dence of  its  presence. 


80  GENERAL    ACTION    OF    POISONS 


Section  II.— Deposit  of  Drugs  in  the  System  through 
Assimilation. 

The  normal  tissues  are  formed  of  solid  and  fluid  ele- 
ments, of  which  the  former  undergo  a  more  gradual  trans- 
formation than  the  latter.  A  foreign  bod}^,  therefore,  will 
have  a  tendency  to  remain  longer  in  the  system  when  it 
becomes  a  part  of  a  formed  tissue  than  when  associated 
with  one  of  the  fluid  elements  ;  and  if  the  part  in  which 
it  is  deposited  is  comparatively  inactive  in  function  (such 
as  the  bone),  it  may  remain  in  the  system  indefinitely 
without  producing  any  symptom  as  a  result  of  its  presence. 
It  is  only  lately  that  examples  of  this  form  of  assimila- 
tion of  poisonous  substances,  w:hich  are  always  inorganic, 
have  attracted  any  attention.  In  such  instances  it  has 
been  found  that  the  inorganic  principles  in  the  animal 
economy  may  be  replaced  by  other  isomorphic  elements. 
As  examples  of  this  may  be  mentioned  the  substitution 
of  lead  and  baryta  salts  for  the  lime  salts  of  the  bones ; 
the  substitution  for  the  phosphates  of  the  isomorphic  salts 
of  arsenious  acid  ;  and  probably  also  the  deposits  of  copper 
in  the  various  organs  are  governed  by  the  same  rules. 
As  regards  the  ultimate  fate  of  such  foreign  ingredients 
of  the  tissues  it  is  probable  that  they  are  finally  replaced 
by  the  normal  constituents  when  the  supply  of  the  poison 
is  interrupted. 


Section  III. — Chemical  Alteration  of  Poisons  in  the 
Economy. 

In  the  case  of  organic  poisons,  and  probably  also  with 
the  inorganic  poisons  in  regard  to  substitutions  in  their 
acids  and  bases,  changes  in  chemical  constitution  occur 
very  frequently. 

These  changes  may  occur  either  at  the  point  of  ab- 
sorption, especially  when  the  poisons  are  administered 
through  the  digestive  apparatus,  only  after  entrance  into 


CHEMICAL    ALTERATION    OF    POISONS.  81 

the  blood,  or  finally  in  special  organs ;  and  it  is  con- 
ceivable that  the  same  poison  may  undergo  various 
changes  in  different  localities.  These  changes  may  con- 
vert a  poisonous  substance  into  one  physiologically  inert ; 
or,  on  the  other  hand,  an  active  principle  may  be  formed 
from  a  substance  in  itself  innoxious ;  or,  again,  the 
modified  form  of  a  poison  may  produce  symptoms  difter- 
ing  from  those  due  to  its  unaltered  state. 

Of  the  various  possible  modifications  in  constitution  of 
a  poison,  those  attributable  to  changes  at  the  point  of 
absorption  are  to  be  first  examined,  and,  as  already  stated, 
the  digestive  apparatus  is  most  liable  to  produce  such 
changes  as  will  convert  a  substance  which  is  harmless 
when  administered  subcutaneously  into  an  active  poi- 
son, or  vice  versa.^  The  character  of  many  of  these 
changes  may  be  indicated  by  their  dependence  on  the 
known  characteristics  of  the  locality  of  administration  ; 
others  can  only  be  determined  by  the  detection  of  their 
products  either  in  the  excreta  or  in  different  tissues. 

a.  Displacement  of  Acids  or  Bases  in  Salts. — 
The  double  decomposition  of  two  salts  in  mixed  solutions, 
by  which  precipitates  are  formed,  or  by  which  insoluble 
bodies  are  thrown  down  while  acids  or  bases  are  set  free 
in  solution,  may  occur  within  the  organism,  governed  by 
the  same  laws  as  prevail  elsewhere;  and  these  changes  by 
rearrangement  of  elements  may  occur  either  at  the  point 
of  absorption  (stomach  or  intestine),  in  the  blood,  the 
tissue,  or  even  in  the  excretory  apparatus.  Since  solu- 
ble salts  occur  in  all  portions  of  the  body,  free  acids  in  sev- 
eral localities,  as  in  the  gastric  juice,  and  free  alkalies  in 
nearly  all  the  animal  juices,  the  administration  of  any  salt, 
alkali, or  acid  offers  an  opportunity  for  the  special  changes 
under  consideration.     And  since  usually  all  soluble  salts 

'  In  this  connection  it  might  bo  mentioned  that  poisonous  sub- 
stances may  be  produced  by  abnormal  fermentations  in  the  ordi- 
nary digestive  processes,  such  as  sulphuretted  liydrogen,  or  pto- 
maines. 


82  GENERAL    ACTION    OF    POISONS. 

of  a  poisonous  base  or  acid  have  the  same  action  as  the 
base  or  acid,  such  changes  are  consequently  only  of  inte- 
rest in  this  connection  when  some  exception  to  this  rule 
occurs,  or  when  precipitates  are  produced  in  the  rear- 
rangement of  molecules ;  such  changes  may  either  lead 
to  the  elimination  of  the  poisonous  principle,  may  render 
it  innoxious,  or  may  mechanically  produce  functional  dis- 
turbances by  forming  emboli. 

h.  Formation  of  Chemical  Compounds  with  Ingre- 
dients OF  THE  Tissues  and  Excretion  under  modified 
Forms. — The  important  discovery  by  Woliler  that  benzoic 
acid,  when  introduced  into  the  system,  appears  in  the 
urine  as  hippuric  acid,  therefore  united  with  glycin,  was 
the  first  example  of  this  kind.  Other  similar  instances 
have  only  a  physiological  interest,  but  should  serve,  in 
the  investigation  of  the  ultimate  fate  of  a  poison,  as  a 
reminder  of  its  possible  destination,  when  no  traces  of  the 
unaltered  poison  or  of  its  oxidation  products  are  to  be 
met  with  in  the  excretions. 

It  is  conceivable  that  to  the  formation  of  such  com- 
pounds, either  the  poisonous  action  of  the  substance  ad- 
ministered, or,  possibly,  its  innoxiousness,  may  be  due. 
No  general  rules  for  the  determination  of  such  conditions 
can  be  given. 

c.  Decomposition  of  Poisons  in  the  System  and 
Excretion  of  the  Decomposition  Products. — In  gene- 
ral all  organic,  and  certain  inorganic,  poisons  are  capa- 
ble of  decomposition,  and  the  question  arises  whether  the 
marked  oxidizing  property  possessed  by  all  the  animal 
tissues  can  be  concerned  in  the  destruction  of  poisons. 
While  formerly  this  was  generally  admitted  without  de- 
monstration, latterly  this  possibility  has  been  distrusted  ; 
because,  on  the  one  hand,  many  poisons  which  were  hith- 
erto supposed  to  be  so  destroyed,  can  now  readily  be  de- 
tected unaltered  in  the  excretions,  and,  on  the  other,  re- 
reliable  physiological  investigations  have  shown  that 
apparently  readily  oxidizable  substances,  such  as  grape- 


CHEMICAL    ALTERATION    OF    POISONS.  83 

sugar,  are  not  thus  consumed  in  the  system.^  Therefore, 
now,  only  when  direct  evidence  of  the  products  of  such  a 
decomposition  is  given,  can  this  idea  of  the  fate  of  a  drug 
be  entertained. 

In  this  relation,  however,  the  distinction  must  be  drawn 
between  complete  and  incomplete  oxidation.  Complete 
oxidation  of  organic  substances  is  always  accompanied 
by  the  formation  of  carbonic  anhydride  and  water,  and 
under  special  circumstances,  by  the  liberation  of  nitrogen, 
and  the  formation  of  sulphuric  and  phosphoric  acids  ;  the 
nitrogen  appears  never  to  be  oxidized,  or  even  to  be 
completely  isolated,  but,  on  the  contrary,  remains  asso- 
ciated with  the  other  elements  with  which  it  was  com- 
bined before  the  process  of  oxidation  took  place,  and 
appears  as  ammonia  or  ammoniacal  compounds  in  the 
excretions. 

Of  these  different  oxidation  products,  carbonic  acid 
is  the  most  readily  detected.  Carbonic  acid  formed 
by  the  oxidation  of  a  poison  can  either  be  added  to 
that  already  formed  in  expired  air,  thus  increasing  its 
proportion,  or  can  be  found  as  carbonates,  especially  al- 
kaline carbonates,  in  the  urine.  Either  of  these  possi- 
bilities can,  however,  only  be  established  with  any  de- 
gree of  reliability  when  extraordinarily  large  amounts 
of  the  poison  are  subjected  to  oxidation  ;  when  there- 
fore only  small  doses  of  the  drug  are  dealt  with,  any  at- 
tempt at  such  determination  is  useless.  The  method  to 
be  employed  is  similar  to  that  employed  in  all  estimations 
of  the  gases  of  respiration. ^  Large  quantities  of  alkaline 
carbonates  are  indicated  in  the  urine  by  an  abnormal  al- 
kaline reaction :  for  their  careful  qualitative  or  quantita- 
tive analysis  see  Hoppe-Seyler,  Analyse,  p.  256. 

The  investigation  as  to  the  incomplete  oxidation  of 
poisons  will  depend  upon  the  detection  of  special  oxida- 

'  Ludwig  and  Scheremetjewski.  Sachs.  Acad.  Sitzgsber,  1869. 
154. 

2  For  simple  methods  see  Kowalewski  and  Sanders-Ezn.  (Sachs. 
Acad.  Sitzgsbr.  1866,  iii.  ;  1867,  68;  1869,  154)  and  Rohry  and 
Zuntz.  (Arch.  f.  d.  Ges.  PhysioL  iv.  57). 


84  GENERAL    ACTION     OF    POISONS. 

tion  products,  such  as  of  aldehyde  for  alcohol,  benzol  or 
phenol  for  acetic  acid,  etc.  Among  the  normal  products 
of  incomplete  oxidation,  whose  increase  is  to  be  looked 
for,  oxalic  acid  deserves  notice.  As  already  stated,  these 
processes  of  oxidation  may  lead  to  the  removal  of  the 
poisonous  principle  from  the  blood,  or  when  the  decom- 
position products  are  themselves  poisons,  to  new  symp- 
toms of  poisoning.  In  the  latter  case  the  symptoms  can 
only  be  attributed  to  such  products  after  the  latter  have 
been  proved  to  be  present. 

d.  Decomposition  of  Poisonous  Substances  and 
Excretion  of  their  Products. — The  animal  organism 
is  rich  in  ferments  which  are  capable  of  causing  hydro- 
lytic  decomposition  of  various  substances  (?.  ^.,  their 
division  with  the  addition  of  water)  ;  and  there  is  no 
doubt  that  poisons,  like  many  of  the  normal  constituents 
of  the  body,  may  be  subjected  to  such  changes,  and  the 
destruction  of  the  poisonous  properties  of  the  drug,  or 
the  creation  of  new  poisonous  principles,  be  thereby  pro- 
duced. Starting-points  for  such  studies  can,  however,  be 
obtained  only  from  the  knowledge  of  the  chemical  pro- 
perties of  the  drug  in  question. 

With  the  outlines  given  above  all  the  possible  changes 
of  the  poison  in  the  economy  are  not  exhausted.  And 
it  cannot  even  be  said  that  a  complete  knowledge  of  the 
fate  of  a  poison  is  possessed  when  its  ultimate  products 
and  the  paths  by  which  they  leave  the  system  are  known. 
In  the  first  place  all  intermediate  changes  should  be 
studied,  and  in  the  second  the  question  will  arise  as  to 
the  location  in  which  these  phases  are  met  with,  and 
especially  the  way  in  which  the  particles  of  the  poison 
produce  their  characteristic  action. 

But  since  we  possess  but  little  knowledge  as  to  the 
changes  in  the  normal  constituents  of  the  body,  we  can 
naturally  not  expect  to  obtain  these  data  for  poisons,  even 
though  the  latter  can  the  more  readily  of  the  two  be  fol- 
lowed   through  the  system  ;    nevertheless  careful  phar- 


SYxMPTOMS    PRODUCED    BY    POISONS.  85 

raacolo<]:ical  studies  of  these  points  will  undoubtedly  ulti- 
mately be  of  the  greatest  assistance  to  physiology.  But  as 
yet,  even  in  the  case  of  substances  most  readily  detected, 
such  as  the  poisonous  metals,  we  know  little  more  than 
that  they  are  excreted  through  the  kidneys  in  some  un- 
known form. 


IV. 

EXPLANATION  OF  THE  SYMPTOMS  PRODUCED  BY  POISONS. 

The  manifestations  of  the  action  of  a  poison  may 
belong  to  one  of  two  classes  :  First.  Those  which  can  be 
attributed  to  local  action  on  the  absorbing  surfaces,  and 
which  are  either  confined  to  the  absorbing  surface,  or 
which  may  be  capable  of  producing  secondary  general 
disturbances  of  function  from  sympathy.  Seco7id.  Gene- 
ral manifestations  in  the  strictest  sense,  and  which  are 
dependent  upon  the  presence  of  the  poison  in  the  blood. 

No  fundamental  points  of  contrast  can  be  made  be- 
tween the  local  and  general  action,  since,  as  already  indi- 
cated, the  general  is  but  the  sura  total  of  all  the  local 
effects  of  the  poison  produced  by  its  entrance  into  the 
blood  and  its  simultaneous  action  on  all  the  organs.* 
When  it  is  remembered,  however,  that  in  the  local  appli- 
cation the  poison  comes  in  contact  with  the  tissues  in  a 
very  different  manner  from  when  introduced  into  the 
blood,  a  partial  separation  of  the  two  groups  of  pheno- 
mena is   rendered  possible.     In  local  applications,  the 

^  For  a  long  time  it  was  believed  that  poisons,  especially  the  nar- 
cotics, were  carried  throughout  the  system  by  the  agency  of  the 
nervous  system.  This  supposition  can,  however,  be  disproved  by 
the  following  experiment :  The  hind  leg  of  a  frog  is  partially  sepa- 
rated from  the  body,  leaving  only  the  sciatic  nerve  intact,  and 
immersed  in  a  solution  of  strychnine,  without  any  symptoms  being 
produced  ;  if,  liowever,  instead  of  the  nerve,  the  bloodvessels  are 
left  intact,  svmptoms  of  poisoning  rapidlv  ensue, 
8 


86  GENERAL    ACTION    OF    POISONS. 

poison  acts  exclusively,  or  at  least  in  the  first  place,  on 
the  superficial  tissues  of  the  organ,  the  degree  of  action 
depending  largely  on  the  concentration  of  the  solution  ; 
while  after  introduction  into  the  blood  it  acts  gradually 
on  all  portions  of  the  organ,  perhaps  weakened  by  dilu- 
tion by  the  blood,  or  by  the  chemical  alterations  to  which 
it  has  been  subjected.  Thus  it  may  happen,  that  a  poison 
will  act  in  various  ways  on  a  single  organ,  according  as 
it  is  directly  applied,  or  carried  to  it  by  the  circulation; 
in  one  case,  possibly,  being  extremely  energetic,  in  the 
other,  completely  inactive.  The  only  method  of  de- 
termining to  which  of  these  modes  of  action  the  symp- 
toms are  due,  if  not  self-evident,  lies  in  change  of  the 
mode  of  administration. 

In  all  cases,  the  symptoms  of  poisoning,  especially  in 
the  warm-blooded  animals,  furnish  a  complex  picture 
which  can  only  be  explained  by  a  systematic  series  of 
experiments ;  it  is  the  object  of  the  following  pages  to 
give  some  general  rules  whereby  such  experiments  can  be 
conducted. 

After  an  answer  to  these  questions  has  been  found, 
and  the  organ  or  organs  determined  on  which  the  poison, 
after  introduction  into  the  circulation,  principally  acts,  and 
the  character  of  the  functional  disturbance  established,  it 
then  remains  to  discover  to  what  physical  or  chemical  pecu- 
liarity of  the  poison  its  action  is  due.  The  reply  to  this 
question,  which  has  as  yet  been  reached  in  but  few  cases, 
will  at  the  same  time  explain  the  reason  of  the  localiza-' 
tion  of  the  poison  in  any  special  organ. 

A  third  important  point  of  inquiry  arising  in  the  care- 
ful study  of  the  action  of  a  drug  concerns  the  mode 
of  recovery  after  poisoning;  that  is,  the  manner  in  which 
the  system,  and  especially  the  aftected  organs,  free  them- 
selves from  the  poison  and  regain  their  normal  condition. 


[After  the  administration  of  the  poison  the  attempt 
should  first  be  made  to  obtain  an  idea  of  the  general 
action  of  the  poison,  so  as  to  facilitate  the   localization 


SYMPTOMS    PRODUCED    BY    POISONS.  87 

and  analysis  of  the  separate  symptoms.  The  animals, 
therefore,  after  receiving  a  dose  of  the  poison,  are  allowed 
to  move  about  (frogs  may  be  placed  under  a  glass  bell- 
jar),  and  notes  made  on  the  different  symptoms  as  they 
appear,  with  reference  to  the  time  elapsing  between  the 
administration  of  the  poison  and  the  advent  of  the  various 
symptoms.  It  should  be  noted  whether  the  animal  is 
restless  and  inclined  to  move  about,  and  whether  his 
movements  appear  normal,  or  unsteady,  weak,  spasmodic, 
etc  ;  or  whether  he  seems  disinclined  to  move,  and  if  so, 
if  the  disinclination  depends  upon  loss  of  power,  pain,  or 
somnolence.  Notes  should  also  bo  made  as  to  occur- 
rence of  vomiting,  purging,  or  micturition,  salivation, 
lachrymation,  state  of  the  pupil,  etc.,  as  perhaps  furnish- 
ing guides  to  the  detection  of  the  specific  action  of  the 
drug.  The  heart  beats  and  respiration  should  be  counted, 
and  any  change  in  character  noted,  and  if  the  drug  prove 
poisonous,  and  the  dose  fatal,  it  should  be  observed 
whether  respiration  ceases  while  the  heart  still  continues 
to  beat,  or  vice  versa.  As  soon  as  possible  after  death, 
the  animal  should  be  opened,  and  the  condition  of  the 
heart,  whether  pulsating  or  not,  or  whether  stopped  in 
systole  or  diastole,  noticed  ;  it  should  also  be  determined 
whether  the  cardiac  and  voluntary  muscles  and  motor 
nerves  preserve  their  irritability  to  various  stimuli, 
whether  the  intestines  are  in  active  peristalsis  or  not, 
and  the  amount  and  color  of  the  blood  in  the  lungs  and 
right  side  of  the  heart. 

If  after  waiting  some  time  no  decisive  results  of  the 
poison  appear,  the  dose  should  be  repeated  at  intervals 
until  the  drug  is  proved  to  be  innocuous,  or  until  some 
effects  have  been  produced.  The  mode  of  administra- 
tion also  should  be  changed  in  either  case  for  the  reasons 
already  given. 

If  the  drug  be  poisonous,  the  next  question  is  to  deter- 
mine the  smallest  dose  capable  of  causing  death.  To 
accomplish  this  an  animal  is  weighed,  a  small  dose 
injected,  and  after  waiting  a  short  time,  the  dose  repeated 
until  death  is  produced :  it  is  then  calculated  how  much 


88  GENERAL    ACTION    OF    POISONS. 

of  the  poison  per  gramme  weight  of  the  animal  was 
necessary  to  prove  fatal.  Another  animal  is  then 
weighed,  and  a  single  dose  of  the  poison,  which  should  be 
a  little  less  per  gramme  weight  than  the  total  amount 
obtained  in  the  previous  experiment,  injected  at  once,  a 
smaller  amount  being  selected  so  as  to  allow  for  possible 
excretion  during  the  intervals  of  the  first  experiment.  If 
this  amount  prove  fatal,  a  still  smaller  proportionate  dose 
is  given  to  another  animal,  until  the  smallest  possible 
dose  capable  of  causing  death  has  been  determined.] 

The  study  of  the  symptoms  of  poisoning  will  naturally 
start  with  the  one  which  is  most  marked.  In  many  cases 
therefore  a  departure  from  the  order  of  investigation  here 
followed  will  be  advisable. 


Section  1.— Action  on  the  Circulatory  Apparatus. 

Direct  examination  of  the  heart  will  furnish  a  means 
of  determining  the  frequency,  strength,  and  rhythm  of 
its  pulsations.  The  first  of  these  points,  and  to  a  certain 
degree  both  the  others,  can  be  ascertained  in  the  larger 
animals  and  in  man,  without  any  operation,  through  pal- 
pation of  the  cardiac  impulse  or  pulse,  or  by  auscultation 
of  the  heart  sounds.  In  animals  the  frequency  of  pulsa- 
tion may  be  rendered  evident  by  inserting  a  long  needle 
through  the  chest  wall  into  the  heart,  when  its  oscillations, 
coinciding  with  the  pulse,  may  either  be  counted,  allowed 
to  register  on  a  revolving  drum,  or  to  strike  a  bell,  thus 
serving  for  demonstration  to  large  audiences.  In  frogs 
it  is  necessary  to  expose  the  heart,  and  this  is  readily 
accomplished  by  removing  with  scissors  a  triangular  piece 
of  the  skin  and  bony  wall  of  the  thorax  over  the  heart 
so  as  to  expose  it  completely  ;  it  is  better  to  leave  the 
pericardium  uninjured.  In  warm-blooded  animals  it  is 
very  difficult  to  expose  the  heart  without  injuring  the 
pleura,  and  even  if  the  operation  should  succeed  it  will 
not  freely  expose  the  heart ;  when,  therefore,  a  careful 
inspection  of  the  heart  is  necessary  in  warm-blooded 
animals  it  is  better  to  freely  open  the  thorax  and  main- 


ACTION    ON    THE    CIRCULATORY    APPARATUS.       89 

tain  artificial  respiration.  The  heart  is  then  readily 
inspected  during  the  pauses  between  inspiration  when 
the  contractino;  luno;s  uncover  it. 

More  satisfactory  results  as  to  the  rapidity  of  the 
heart's  pulsations  and  its  relation  to  various  conditions  of 
the  vascular  system  are  obtained  by  the  graphic  method. 
This  is  accomplished  either  by  the  Marey  or  Pond 
sphygmograph  applied  over  an  artery,  the  cardiograph 
over  the  cardiac  impulse,  or  the  Ludwig  or  Fick  mano- 
meter connected  with  an  artery  and  serving  to  register 
the  oscillations  of  blood-pressure  on  the  kymographion. 

[The  best  form  of  cardiograph  is  that  of  Marey  and 
Chauveau   as   modified   by   Sanderson    (Fig.   16).      It 

Fig.  16. 


Sanderson's  cardiograph. 

consists  of  a  shallow  disk-shaped  box  of  metal,  the  top  of 
which  is  closed  by  a  rubber  membrane,  while  its  interior 
communicates  with  a  small  rectangular  tube  inserted  in 
the  bottom.  Fastened  to  the  bottom  of  the  box  is  a  flat 
steel  spring,  bent  on  itself  twice  at  right  angles  so  that 
its  free  extremity,  which  is  perforated  by  a  steel  screw 
carrying  a  large  button  is  opposite  the  centre  of  the 
membrane,  where  the  latter  is  protected  by  a  thin  disk 
of  metal. 

The   box  or  tympanum   is  also  provided  with  three 


90 


GENERAL    ACTION    OF    POISONS. 


¥Ur   17, 


levelling  screws  and  tapes  to  fasten 
it  to  the  body.  When  an  observation 
is  to  be  made,  the  instrument  is  bound 
to  the  chest  so  that  the  knob  on  the 
head  of  the  centre  screw  lies  exactly 
over  the  point  of  cardiac  impulse. 
The  rectangular  tube  is  then  connect- 
ed by  means  of  rubber  tubing  with 
Marey's  tympanum  and  lever  (Fig. 
1 7),  an  instrument  constructed  on  the 
same  principle  as  the  cardiograph,  with 
the  exception  that  the  movements  of  its 
rubber  membrane  are  communicated 
to  a  lever  by  which  they  can  be  re- 
corded on  a  revolving  drum  covered 
with  smoked  paper.  When  now  the 
levelling  screws  are  so  adjusted  that 
the  head  of  the  screw  passing  through 
the  spring  presses  on  the  chest  wall 
while  its  point  is  in  contact  with  the 
rubber  membrane,  every  elevation 
in  the  chest  wall  will  produce  a  cor- 
responding depression  in  the  rubber 
membrane,  thus  diminishing  the  size 
of  the  cavity  of  the  tympanum  and 
forcing  some  of  its  contained  air  into 
the  second  tympanum  whose  mem- 
brane will  be  proportionately  expand- 
ed, its  motion  being  magnified  by  the 
lever  resting  on  it. 

When,  therefore,  a  tracing  is 
taken  of  the  cardiac  impulse,  it  will 
be  found  that  the  systole  of  the  heart 
is  always  indicated  by  a  sudden  as- 
cent of  the  lever,  and  the  diastole  by 
a  gradual  fall.  With  the  apparatus 
so  arranged  studies  may  be  made  on 


Fig,  17.— Marey's  tympannrn  and  lever. 


ACTION    ON    THE    CTRCULATORY    APPARATUS.       91 

the  effect  of  drugs  not  only  on  the  absolute  rate  of  pul- 
sation of  the  heart,  but  also  on  the  relative  duration  of 
the  ventricular  systole  and  diastole.  Care  must  be  taken, 
however,  not  to  attribute  all  changes  from  this  normal 
simple  curve  to  toxic  action ;  for  if  the  cardiograph  be- 
comes at  all  shifted,  so  that  the  button  lies  to  one  side  of 
the  impulse,  the  character  of  the  tracing  will  be  entirely 
changed.  For  here,  while  we  still  obtain  a  sharp  ascent 
of  the  lever  corresponding  to  the  ventricular  systole,  the 
rise  is  immediately  followed  by  a  sudden  fall,  due  to  the 
recession  of  the  chest-wall  in  the  production  of  the  so- 
called  negative  impulse. 

The  purpose  of  the  sphygmograph  is  to  represent 
graphically  the  succession  of  expansions  and  contrac- 
tions which  occur  in  the  artery  consequent  to  each  car- 
diac systole  ;  its  use  and  construction  are  so  well  known 
as  to  require  no  description  here.] 

The  sphygmograph  has  the  advantage  that  it  requires 
no  operation  for  its  use,  and  can  therefore  be  employed 
in  experiments  made  on  man ;  and  both  the  sphygmograph 
and  cardiograph,  on  careful  analysis  of  their  curves,  give 
information  not  only  as  to  the  frequency  of  the  heart's 
pulsations  but  also  as  to  the  duration  and  characteristics 
of  the  single  periods  of  each  cardiac  contraction. 

Although  these  instruments  are  valuable  as  furnishing 
a  means  of  studying  the  different  times  of  the  heart's 
beat,  yet  the  force  of  the  beats  can  only  be  measured 
with  manometers,  either  the  simple  hsemodynamometer,  or 
recording  manometer  (kymographion). 

The  kymographion  serves  to  measure  the  blood-pres- 
sure in  an  artery,  besides  enabling  the  frequency  of 
pulsation  to  be  counted.  The  blood-pressure  is  dependent 
not  only  on  the  strength  and  frequency  of  the  heart's 
action,  but  also  on  the  condition  of  the  general  vascular 
system  ;  every  contraction  in  the  arterial  system,  whether 
general  or  confined  to  a  single  extended  portion  of  the 
body,  produces  an  increase  in  arterial  blood  tension. 
So  the  results  obtained  by  kymographic  measurements 


92  GENERAL    ACTION    OF    POISONS. 

cannot  be  attributed  directly  to  the  heart,  but  will  depend 
upon  the  condition  of  the  arterial  system  at  large. 

Mode  of  Conducting  an  Experiment  on  Blood- 
Pressure. — [The  tension  of  blood  within  the  arterial 
system  may  be  measured  in  various  ways  ;  either  by  the 
primitive  method  of  Hale,  who  simply  connected  a  long 
vertical  glass  tube  with  an  artery  and  noted  the  height 
to  which  the  column  of  blood  rose,  or  by  the  cardiometer 
of  Poiseuille,  or  the  haemodynamometer  of  Bernard  ;  the 
improved  manometers  of  Ludwig  and  Fick  marked  such 
an  advance  in  this  line  of  investigation  that  one  or  the 
other  of  their  instruments  is  now  invariably  used. 

Ludwig's  manometer  (Fig.  18)  consists  of  two  com- 
municating  glass  tubes  m  and  m',  partially  filled  with 
distilled  mercury,  inserted  into  a  block  of  steel  in  which 
a  cavity  is  hollowed  out  which  communicates  with  the 
interior  of  the  two  glass  tubes  ;  below  is  an  opening 
closed  by  a  steel  screw  which  can  be  removed  when  the 
instrument  requires  cleaning.  To  the  left  the  glass  tube 
communicates  with  a  flexible  leaden  tube  ^,  a  stop-cock  c 
intervening,  which  is  connected  with  the  artery  in  which 
it  is  desired  to  measure  the  blood-pressure.  The  mercury 
in  the  arm  m'  of  the  manometer  bears  on  its  surface  an 
ivory  float  connected  with  a  long  slender  steel  rod  carry- 
ing the  pen  |.>,  for  recording  the  movements  of  the  column 
of  mercury  on  the  revolving  surface  r.  At  pb  is  a  box 
containing  a  pressure-bottle,  filled  with  a  saturated  solu- 
tion of  sodium  carbonate,  which  can  be  elevated  or  de- 
pressed at  pleasure. 

The  entire  system  of  tubes  between  the  surface  of  the 
mercury  in  the  tube  m  of  the  manometer  and  the  artery 
and  pressure-bottle  being  filled  with  sodium  carbonate, 
by  which  the  blood  is  prevented  from  clotting,  the  clamp 
<?"  being  closed  and  the  stop  cock  e  and  the  clamp  on  the 
artery  opened,  the  column  of  mercury  in  the  distal  arm  of 
the  manometer  rises  to  a  point  which  indicates  the  blood- 
pressure,  while  its  oscillations  indicate  the  rapidity  of 
the  heart's  pulsations.     As,  however,  these  variations  in 


ACTION    ON    THE    CIRCULATORY    APPARATUS.      93 


94  GENERAL    ACTION    OF    POISONS. 

pressure  produced  by  the  heart's  pulsations  are  in  most 
animals  too  rapid  to  be  counted  by  the  unaided  eye,  the 
movements  of  the  column  of  mercury  are  recorded  by  the 
pen  on  the  moving  surface,  the  vertical  height  of  the 
tracing  thus  produced  indicating  the  blood-pressure  while 
the  distance  between  the  breaks  in  this  line,  the  rate  of 
motion  of  the  recording  surface  being  known,  will  give 
the  time  elapsing  between  each  cardiac  revolution. 

The  disadvantage  of  all  forms  of  mercurial  manometer 
is  that  the  inertia  of  the  mercury  is  so  great  that  it  does 
not  give  the  true  form  or  extent  of  the  variations  in  blood 
pressure  which  accompany  each  beat  of  the  heart. 
Hence  the  use  of  the  mercurial  manometer  is  restricted 
to  the  investigation  of  those  changes  in  mean  arterial 
pressure  which  are  not  interfered  with  by  the  proper 
oscillations  of  the  instrument,  that  is,  when  they  do  not 
recur  with  too  great  rapidity  ;  while  it  must  be  remem- 
bered that  the  curve  is  not  that  produced  by  the  actual 
movement  of  the  arterial  column,  but  of  the  mercury. 
For  while  the  artery  expands  suddenly  the  mercury  rises 
slowly,  and  before  the  latter  has  attained  its  highest 
point  the  artery  will  have  collapsed  and  the  falling  column 
of  mercury  will  meet  an  expanding  force  in  the  artery. 
Hence,  when  the  heart's  beats  are  very  rapid,  the  oscil- 
lations of  the  mercurial  column  will  be  relatively  too 
small  in  extent,  while  when  the  heart  beats  slowly,  they 
will  be  exaggerated. 

Wliile,  therefore,  the  mercurial  manometer  answers 
perfectly  well  for  the  study  of  the  mean  arterial  pressure 
and  change  in  the  number  of  cardiac  pulsations,  exact  in- 
formation as  to  the  changes  in  the  arterial  system  during 
each  pulsation  can  only  be  obtained  by  the  use  of  Fick's 
spring  manometer  (Fig.  19).  This  consists  essentially 
of  a  C-shaped  hollow  spring  of  thin  metal  a,  filled  with 
alcohol,  and  connected,  by  a  leaden  tube  attached  to  c 
and  filled  with  sodium  carbonate  solution,  with  the  artery. 

Each  variation  in  the  arterial  pressure  will  cause  an 
expansion  or  contraction  of  the  spring,  whose  movements, 
magnified  by  a  lever  Z,  may  be  recorded  on  the  revolving 


ACTION    ON    THE    CIRCULATORY    APPARATUS.       95 


drum  ;  before  use,  this  manometer  must  be  graduated  by 
comparison  with  a  mercurial  manometer.  In  ordinary 
pharmacological  work  the  mercurial  manometer  is  suffi- 
ciently accurate. 

Fig.  19. 


Fick's  spring  iniinometer.     (From  Foster's  Physiology.) 

The  present  important  system  of  recording  known  as 
the  "  graphic  method"  started  with  the  simple  revolving 
drum  of  Ludwig,  and  while  to  him  belongs  the  credit  of 
having  first  introduced  this  method  into  physiological  ex- 
perimentation, to  him  also  do  we  owe  the  majority  of  the 
modern  improvements  in  recording  apparatus  as  now 
used. 

The  kymographions  in  general  use  in  the  physiological 
laboratory  for  studies  of  blood-pressure  are  of  two  kinds: 


96  GENERAL    ACTION    OF    POISONS. 

Fig.  20. 
d 


Ludwig's  kyinogiaiiliiou.     (From  Cyou's  Methodik.) 


ACTION    ON    THE    CIRCULATORY     APPARATUS.       97 

in  one  the  manometer  pen  traces  its  movements  on  a  re- 
volving drum  covered  with  smoked  paper  ;  in  the  other, 
the  pen  contains  ink  and  describes  its  curves  on  a  uni- 
formly moving  surface  of  unglazed  paper. 

The  first  of  these  instruments  is  represented  in  Fig.  20. 
Tiie  clock-work  contained  in  the  case  ^  sets  the  revolving 
disk  D  in  motion  and  transfers  its  movements  by  means 
of  the  friction  rollers  n  and  n'  to  the  metal  drum  R.  The 
position  of  this  drum  can  be  changed  at  will  by  means  of 
the  screw  L\,  while  its  rate  of  revolution  may  be  gradu- 
ated by  the  screw  i/  (it  of  course  moving  more  rapidly 
when  the  friction  rollers  are  at  the  circumference  of  the 
disk  than  when  at  its  centre),  and  by  adjusting  the  clock- 
work. Two  drums  are  usually  supplied  with  each  instru- 
ment, so  that  Avhen  one  is  filled  it  can  be  removed  by 
raivsing  the  clamp  d  and  the  other  substituted.  At  Z  is 
seen  the  mercurial  manometer. 

To  obtain  information  as  to  the  mean  arterial  pressure 
all  that  is  necessary  is  to  allow  the  manometer  to  write 
on  the  revolving  surface,  when  the  height  of  the  curve 
above  the  abscissa  will  give  the  desired  information ;  but 
studies  of  changes  in  the  pulse  as  well  as  of  the  times 
of  blood-pressure  variations,  require  that  the  rate  of 
motion  should  also  be  recorded  on  the  drum.  Nearly  all 
forms  of  such  time-recorders,  when  employed  for  this  pur- 
pose, are  modifications  of  the  simple  electro-magnet,  first 
used  by  Dr.  Locke,  of  Cincinnati ;  nearly  any  form  of 
electro-magnet,  such  as  a  telegraph  sounder,  can  be  made 
to  answer  this  purpose  by  attaching  a  light  lever  to  the 
keeper,  and  allowing  it  to  record  its  motions  on  the  drum ; 
for  use  as  a  time-marker,  the  current  through  the  electro- 
magnet must  of  course  be  interrupted  at  regular,  known 
intervals  by  an  electric  metronome,  or  by  any  of  the 
various  automatic  current-interrupters.  For  description 
of  such  instruments,  reference  must  be  made  to  some  of 
the  various  hand-books  for  the  physiological  laboratory.^ 

'  A  simple  form  of  automatic  current  interrupter,  employed  by  the 
Translator,  is  described  in  the  Medical  News,  Sept.  30, 1882,  p.  370. 
9 


98 


GENERAL    ACTION    OF    POISONS. 


The  large  kymoorraphion  with  continuous  roll  of  paper  is 
represented  in  Fig.  21. 

Fig.  21. 


Large  kyrnographion,  for  continuous  tracings.  (From  Foster's  Physiology.) 
The  clock-work  machinery,  some  of  the  details  of  which  are  seen,  unrolls  the 
paper  from  the  roll  C,  carries  it  smoothly  over  the  cylinder  B,and  then  winds  it 
up  into  the  roll  A.  Two  electro-magnetic  markers  are  seen  in  the  position  in 
which  they  record  their  movements  on  the  paper  as  it  travels  over  B.  The  man- 
ometer, or  any  other  recording  instrument  used,  can  be  fixed  either  in  the  notch 
in  front  of  B  or  in  any  other  position  that  may  he  desired. 

Details  of  Blood-Pressure  Experiments. — Blood- 
pressure  experiments  may  be  made  on  dogs,  cats,  or  rab- 
bits, the  artery  selected  being  either  the  carotid  or  fem- 
oral. 

When  the  small  kyrnographion  is  used,  both  drums 
should  be  smoothly  covered,  before  commencing  the  ope- 
ration, with  strips  of  glazed  paper  of  the  width  of  the 
drum  and  a  little  longer  than  the  drum's  circumference, 
and  the  overlapping  ends  fastened  with  mucilage,  care 
being  taken  that  the  paper  is  not  pasted  to  the  drum,  or 
it  will  be  impossible  to  remove  the  paper  after  the  exper- 


ACTION    ON    THE    CIRCULATORY    APPARATUS.       99 


iment  without  damaging  the  tracings.  The  drums  are 
then  smoked  by  revolving  them  rapidly  in  the  flame  of 
a  coal-oil  lamp,  or  in  that  of  burning  camphor,  until  they 
are  covered  with  a  uniform  coating  of  soot ;  it  is  better 
not  to  coat  the  drums  too  heavily,  or  the  friction  will  be 
so  great  that  a  clear  tracing  cannot  be  obtained.  One 
drum  is  then  placed  in  position  and  the  clock-work  wound 
up.  When  the  large  kymographion  is  used,  the  paper 
is  of  course  not  smoked,  the  tracings  being  made  with 
glass  pens  filled  with  a  one  per  cent,  aniline  solution. 

The  animal  is  then  fastened  on  its  back  and  a  canula 
inserted  in  the  usual  manner  into  the  carotid  or  femoral 
artery,  care  being  taken  in  the  former  case  not  to  injure 
the  important  cardiac  nerves  lying  in  the  carotid  sheath  ; 
a  second  canula,  fitting  the  nozzle  of  the  injection  syringe, 
is  then  inserted  into  the  jugular  vein. 

The  test  should  then  be  made,  by  closing  the  end  of  the 
tube  t  with  the  finger  and  rapidly  compressing  it  at  an- 
other point  with  the  fingers  of  the  other  hand,  as  to 
whether  the  manometer  pen  rides  freely  on  the  surface  of 
the  mercury ;  the  observance  of  this  precaution  will  save 
a  great  deal  of  annoyance  in  the  course  of  the  experi- 
ment from  clogging  of  the  mercury  around  the  float ;  no 
experiment  should  ever  be  commenced  until  all  the  ap- 
paratus has  been  tested  and  found  in  perfect  working 
order. 

The  manometer  pen  is  held  in  contact  with  the  revolv- 
ing surface  by  means  of  a  little  lead  plummet  attached 
by  a  thread  to  the  brass  rod  seen  at  x  on  the  top  of  the 
kymographion ;  this  rod  must  of  course  be  moved  until  its 
extremity  is  vertically  above  the  manometer  pen.  After 
having  seen  that  the  current-interrupter  and  electro-mag- 
netic time-marker  are  in  good  working  order,  the  latter 
is  so  adjusted  as  to  write  on  the  drum  vertically  under 
the  manometer  pen,  and  at  a  height  corresponding  with 
the  level  of  the  latter  when  both  columns  of  mercury  are 
of  the  same  height ;  the  line  then  described  by  the  time- 
marker  will  serve  as  an  abscissa,  or  line  from  which  the 
blood-pressure  is  measured. 


100  GENERAL    ACTION    OF    POISONS. 

The  pens  should  barely  touch  the  smoked  surface  so 
as  to  interfere  as  little  as  possible  by  friction  with  the 
motion  of  the  drum. 

At  the  outset  of  the  experiment  the  drum  should  be 
screwed  up  until  it  occupies  its  highest  possible  position. 

When,  as  in  the  diagram,  the  tube  which  contains  the 
soda  solution  ends  in  a  simple  clamp,  the  arterial  canula 
must  be  first  completely  filled  with  soda  solution  by 
means  of  a  pipette,  and  tlien  the  clamp  c"  opened  until  all 
the  air  is  expelled  from  the  tubes,  and  while  the  soda 
solution  is  still  running,  taking  care  that  none  flows 
into  the  wound,  the  end  of  the  tube  t  is  to  be  slipped 
over  the  arterial  canula  and  the  clamp  d  fastened  :  by 
this  means  the  entire  system  of  tubes  from  the  artery  to 
the  surface  of  the  mercury  is  completely  filled  with  soda 
solution,  it  being  very  important  that  no  air  bubbles  are 
present.  The  stop  c  is  now  opened  and  the  pressure 
bottle  raised  until  the  height  of  the  distal  column  of  mer* 
cury  indicates  a  pressure  a  little  less  than  the  expected 
blood  pressure  :  it  is  important  that  the  tubes  should  be 
filled  with  fluid  under  pressure,  otherwise  the  blood,  when 
the  arterial  canula  is  opened,  would  flow  into  the  tubes 
and  so  tend  to  clot,  while  it  is  also  important  that  this 
pressure  should  not  be  greater  than  that  to  which  the 
blood  is  subjected  in  the  vessels,  or  the  soda  solution 
would  flow  into  the  arteries. 

After  this  point  has  been  attended  to,  the  clamp  (/'  is 
closed  and  then  the  clip  or  slip-noose  on  the  artery 
loosened :  the  column  of  mercury  will  now  rapidly  rise  a 
short  distance  and  be  the  seat  of  rapid  oscillations  depend- 
ing on  the  heart's  beats,  while  larger  curves  of  movement 
will  be  superimposed  upon  these  by  the  respiratory 
movements. 

The  canula  inserted  into  the  vein  is  then  filled  by 
means  of  a  pipette  with  the  solution  to  be  injected  so  as 
to  exclude  air,  and  the  nozzle  of  the  filled  injecting  syringe 
inserted  and  bound  fast. 

If,  during  this  procedure,  it  is  found  that  the  arterial 
pressure  has  remained  constant,  the  drum  may  be  started, 
the  time  of  starting  being  written  on  the  drum  ;  after 


ACTION    ON    THE    CIRCULATORY    APPARATUS.      101 

fifteen  or  twenty  seconds  have  passed  the  clip  or  noose 
can  be  removed  from  the  jugular  vein  and  the  dose 
of  the  poison  injected,  the  beginning  and  end  of  the 
injection  and  the  amount  injected  being  marked  on  the 
drum.  After  the  drum  has  made  a  complete  revolu- 
tion, it  may  be  depressed  by  means  of  the  screw  u,  so 
as  to  furnish  a  fresh  surface  for  the  tracing.  If  no  effect 
followed  the  first  dose  a  second  may  now  be  given,  and 
the  doses  may  be  repeated  at  the  desired  intervals. 
When  one  drum  is  filled  with  tracings,  the  clock-work  is 
stopped,  the  time  being  written  on  the  drum,  the  drum 
removed  and  a  fresh  one  substituted ;  in  this  way  trac- 
ings may  be  taken  for  several  hours  in  succession. 

The  paper  is  removed  from  the  drum  by  cutting  with 
a  sharp  knife  and  the  tracing  fixed  by  passing  the  paper 
through  a  bath  of  shellac  dissolved  in  alcohol,  and  then 
suspending  the  papers  until  dry. 

Occasionally,  during  the  course  of  an  experiment,  a 
clot  will  form  in  the  canula  and  prevent  the  registration 
of  the  pulse  and  pressure  curves.  When  this  occurs, 
if  the  above  described  forms  of  canulse  are  used,  a  clip 
must  be  placed  on  the  artery  and  the  canula  removed 
and  washed  out  by  allowing  the  soda  solution  to  flow 
through  it,  though  sometimes  the  clot  may  be  displaced 
by  undoing  the  clamp  cl,  and  picking  out  the  clot  with  a 
bristle  or  straw  ;  before  recommencing  the  experiment, 
the  apparatus  must  again  be  arranged  as  before. 

To  prevent  this  inconvenience  and  loss  of  time  in  re- 
moving canulae  to  displace  blood-clots,  it  is  a  great  ad- 
vantage to  employ  between  the  arterial  canula  and  the 
clamp  on  the  tube  t,  a  canula  similar  to  the  one  repre- 
sented in  Fig.  22.  This  consists  of  a  T-tube  of  silver, 
of  which  the  shorter  arm  is  bound  into  the  tube  t  while 
the  end  a  is  inserted  into  the  arterial  canula ;  the  end  b 
is  closed  by  a  plug ;  and  the  line  shown  in  section  re- 
presents a  partition.  When  now  a  clot  forms  in  the 
arterial  canula  or  in  the  tubes,  a  clip  is  placed  on  the 
artery,   and   the   plug  b  withdrawn  ;  the  soda  solution 


102  GENERAL    ACTION    OF    POISONS. 

then  running  in  the  direction  indicated  by  the  arrows 
usually  serves  to  wash  out  any  clots. 


ZD«f 


In  order  to  facilitate  the  deduction  and  comparison  of 
results  obtained  in  the  above  method,  it  is  necessary  to 
tabulate  the  curves.  Several  plans  may  be  pursued  ; 
the  simplest,  and  one  sufficiently  accurate  for  all  general 
purposes,  is  as  follows  :  The  line  described  by  the  second- 
marker  is  divided  off  into  units  of  fifteen  seconds,  and 
perpendiculars,  intersecting  the  pulse-curve,  erected  at 
the  commencement  of  each  of  these  spaces  ;  each  break 
in  the  manometer  tracing  represents  a  single  contraction 
of  the  heart,  and  the  number  of  these  breaks  between 
two  perpendiculars  will  give  the  number  of  heart- beats 
in  fifteen  seconds.  The  mean  blood-pressure  in  any 
fifteen  seconds  may  be  determined  by  measuring  the  dis- 
tance between  the  time-line,  which  serves  as  the  abscissa, 
and  the  highest  and  lowest  points  on  the  manometer  trac- 
ing between  two  perpendiculars  and  adding  them  together: 
the  two  measurements  are  made  because  of  course  the 
tracing  simply  gives  the  height  of  ascent  in  one  arm  of 
the  manometer,  while  since  the  mercury  falls  to  a  corres- 
ponding extent  in  the  opposite  arm,  the  blood  in  the  ves- 
sels is  always  sustaining  a  pressure  of  a  column  of  mer- 
cury of  double  the  height  of  the  tracing  above  the 
abscissa.  The  results  thus  obtained  are  then  tabulated 
as  follows  :  it  being  noticed  that  in  this  instance  the  time 
is  divided  into  periods  of  ten  seconds,  while  the  lower  line 
represents  the  abscissa.  The  tracing  is  to  be  counted 
from  right  to  left.     (Fig.  23.) 


ACTION    ON    THE    CIRCULATORY    APPARATUS 


103 


104 


GENERAL    ACTION    OF    POISONS. 


Experiment.     No.     Date. 

Large  male  rabbit ;  weight      grms.     Canula  in  the  left  carotid 
oanula  in  the  jugular  vein.     Animal  otherwise  uninjured. 


Blood 

Time. 

Time  after 

pressure 
in  mm.  of 

Pulse  in 

Injectiou, 

mercury. 

15". 

12:0: 

15 

135 

42 

12:  0: 

25 

io 

95 

18 

12:0  : 

35 

20  sec. 

65 

16 

Remarks. 


0.025  grm.  Sanguinarina 
sulph.  injected  into  jugu- 
lar towardstthe  heart. 


Or  the  results  may  be  plotted  to  scale  on  profile  milli- 
meter paper. 

When  it  is  found  that  both  pulse  and  pressure  are 
remaining  constant,  it  is  of  course  not  necessary  to  tabu- 
late long  rows  of  figures  which  show  no  change  ;  account 
should,  however,  always  be  kept  of  the  time  elapsing  be- 
tween different  tracings. 

The  respirations  may  also  often  be  counted  in  these 
experiments,  as  seen  in  the  respiratory  waves  in  the 
manometer  tracing. 

It  is  not  claimed  that  the  method  above  given,  though 
sufficiently  correct  for  general  purposes,  furnishes  a  means 
of  accurately  measuring  the  blood-pressure.  The  mean 
pressure  is  most  accurately  obtained  by  means  of  a  plani- 
meter.  Another  method  is  to  determine  the  square 
superficies  of  the  irregular  figure  bounded  by  the  ab- 
scissa, the  curve  and  the  two  perpendiculars,  and  then 
divide  it  by  the  length  of  the  abscissa.  The  size  of  the 
figure  may  be  determined  by  placing  over  it  a  piece  of 
tracing  paper  or  glass  ruled  in  square  millimeters,  and 
counting  the  number  of  squares  contained  in  it.  In  very 
accurate  experiments,  the  weight  of  the  column  of  sodium 
carbonate  in  the  manometer  should  also  be  deducted  ; 
when  a  solution  of  sp.  gr.  1015  is  used,  this  fraction 
amounts  to  about  ^  of  the  whole.] 

The  action  of  a  poison  on  the  heart  may  be  manifested 
either  in  alterations  in  its  frequency  of  pulsation  (accele- 


ACTION    ON    THE    CIRCULATORY    APPARATUS.       105 

ration,  retardation,  or  arrest  in  systole  or  diastole),  in 
alterations  in  the  strength  of  contraction,  in  disturb- 
ances of  the  normal  cardiac  rhythm  (for  instance,  each 
ventricular  systole  may  be  preceded  by  two  auricu- 
lar contractions,  etc.),  or  in  various  changes  from  the 
normal  blood-pressure.  The  majority  of  heart  poisons 
produce  first  acceleration,  then  retardation,  and  finally 
irregularity,  loss  of  power  and  arrest  of  the  cardiac 
pulsations. 

Causes  of  the  Changes  in  the  Circulatory 
Mechanism.^ 

[Before  we  attempt  to  discover  the  organ  or  organs  to 
whose  functional  disturbance  the  results  produced  by 
the  drug  on  the  circulatory  mechanism  are  due,  it  may 
be  well  to  first  give  a  short  outline  of  the  possible  causes 
of  variation  in  blood-pressure  and  pulse-rate. 

In  the  first  place,  it  must  be  remembered  that  the  blood- 
pressure  depends  not  only  on  the  amount  of  blood  pumped 
into  the  arteries,  but  also  on  the  amount  of  blood  which 
flows  in  the  same  time  into  the  veins  :  Consequently  the 
blood-pressure  may  be  raised,  1,  by  the  heart  beating 
more  quickly ;  2,  by  a  larger  amount  of  blood  being 
pumped  into  the  adrta  by  each  beat ;  8,  by  preventing  the 
escape  of  arterial  blood  into  the  veins  from  contraction  of 
the  small  arteries.  And  blood-pressure  may  be  lowered 
by,  1,  a  slow  rate  of  cardiac  pulsation ;  2,  by  imperfect 
ventricular  contraction,  whereby  only  a  small  amount  of 
blood  is  pumped  into  the  aorta  at  each  pulsation  ;  3,  by 
relaxation  of  the  small  arteries,  whereby  the  escape  of 
blood  into  the  veins  is  facilitated ;  4,  by  obstructed  pul- 
monary circulation. 

One  or  the  other,  or  may  be  several,  of  these  physical 
causes  will  always  lie  at  the  bottom  of  all  variations  in 
blood-pressure.     But  as  we  know  that  both   the  rate  of 

^  In  the  preparation  of  tliis  section,  the  Translator  has  made  free 
use  ot  Dr.  Lauder-Brunton's  lectures  on  "  The  Action  of  Drags  on 
the  Circulation." 


106  GENERAL    ACTION    OF    POISONS. 

the  heart's  contraction  and  the  condition  of  the  small 
arteries  depend  upon  impulses  coming  from  the  nervous 
system,  we  will  find  that  circulatory  disturbances  pro- 
duced by  drugs  are  usually  due  to  some  interference  with 
the  regulating  nervous  mechanism,  though  there  exists 
the  possibility  of  direct  action  on  the  muscular  tissue  of 
the  heart  or  of  the  arteries. 

The  nervous  regulating  mechanisms  of  the  heart  are 
found  in  the  cardiac  ganglia,  the  inhibitory  nerves,  the 
accelerating  nerves,  and  the  vaso-motor  system. 

1.  The  Cardiac  Ganglia. — That  the  heaVt  contains 
within  itself  the  conditions  necessary  for  its  rhythmical 
movement  is  a  fact  whose  knowledge  dates  from  the  time 
of  Galen,  but  that  the  explanation  of  this  phenomenon  lies 
in  the  function  of  automatic  nervous  centres  situated  in 
the  walls  of  the  heart,  was  first  pointed  out  by  Remak. 
These  cardiac  ganglia  are  three  in  number,  and  are  of 
different  functions  ;  two  are  motor  ganglia,  one  an  in- 
hibitory ganglion.  The  motor  ganglia  are  the  ganglion 
of  Remak,  situated  at  the  opening  of  the  inferior  vena 
cava,  and  the  o:anglion  of  Bidder  situated  in  the  left 
auriculo-ventricular  septum ;  the  inhibitory  ganglion  of 
the  heart,  that  of  Ludwig,  is  situated  in  the  inter-auricular 
septum.  These  ganglia  are  not  only  automatic  in  func- 
tion, but  are  also  under  the  control  of,  or  capable  of  being 
modified  by  impressions  coming 
Fig.  24.  from  the  central  nervous   system, 

and  by  varying  conditions  in  the 
temperature  and  chemical  compo- 
sition of  the  blood. 

The  elaborate  studies  of  Schmie- 
deberg  on  heart  poisons  have  ren- 
dered necessary  the  assumption  of 
a  still  more  complicated  system  of 
intrinsic  cardiac  nervous  system; 
this  hypothetical  nervous  appara- 
Diagramoi  the  hypotheti-  ^us  is  represented  in  the  diagram, 

cal  uervous  apparatus  of  the    Fig.  24.       (BrUUtOU.} 

i'«art.  f  he  motor  ganglion  M  maintains 


ACTION    ON    THE    CIRCULATORY    APPARATUS.       107 

the  rhythmical  contraction  of  the  muscular  fibres  of  the 
heart  with  which  it  is  in  connection  through  the  fibres  E. 
This  motor  ganglion  is  connected  by  an  intermediate  ap- 
paratus with  the  inhibitory  ganglion  I,  and  the  latter  by 
the  fibres  A  with  the  centrifugal  inhibitory  influence  pass- 
ing through  the  pneumogastric  nerves  ;  by  means  of  this 
mechanism  the  motor  impulses  generated  by  the  ganglion 
M  may  be  arrested  or  retarded.  The  ganglion  M  is  further 
connected  by  an  analogous  apparatus  with  the  accelerator 
ganglion  Q,  and  the  latter  by  the  fibres  a'  with  the  acce- 
lerator nerves  coming  from  the  medulla  and  sympathetic 
nervous  system. 

It  is  possible  for  poisons  to  produce  cardiac  disturb- 
ance by  interference  with  the  functions  of  any  one  part 
of  this  apparatus ;  the  methods  for  determining  what 
structures  are  aftected  will  be  subsequently  given. 

2.  The  Cardiac  Inhibitory  Nerves. — The  inhibi- 
tory nerves  of  the  heart  arise  in  the  cardio-inhibitory 
centre  in  the  floor  of  the  fourth  ventricle  and  reach  the 
heart  through  the  pneumogastric  nerves ;  when  they  are 
irritated  the  pulse  is  slowed,  or  the  heart  may  be  arrested 
in  diastole.  In  man  and  the  dog,  cat  and  rabbit,  they  are 
in  constant  action,  and  when  divided,  the  heart  beats  more 
rapidly;  the  increase  in  the  pulse  after  section  or  paraly- 
sis of  the  vagi  is  more  marked  in  the  dog  than  in  the  cat 
or  rabbit. 

Drugs  may  render  the  heart's  pulsation  slow  by,  1, 
dh^ect  irritation  of  these  inhibitory  fibres  either,  a,  at 
their  origin  in  the  medulla,  h^  in  their  path  through  the 
vagi,  or,  c^  in  their  terminal  fibres  in  the  heart. 

Or  2,  the  pncumogastrics  may  be  iiidireetly  irritated 
through  the  action  of  the  drug  on  other  parts,  producing, 
<2,  increased  blood-pressure,  or,  6,  accumulation  of  carbonic 
acid  in  the  blood. 

8.  The  inhibitory  nerves  may  be  reflexly  irritated 
through  stimulation  of  sensory  nerves,  irritation  of  the 
intestines,  of  the  sympathetic,  of  the  depressor  nerve,  or 
of  the  vagus  of  the  opposite  side. 

On  the  other  hand,  drugs  may  paralyze  any  point  in 


108 


GENERAL    ACTION    OF    POISONS, 


the  course  of  the  inhibitor}^  fibres,  and  thus  quicken  the 
heart. 

Fig.  25. 


Cft. 


l/ntihcn 


Diagram  of  the  last  cervical  and  first  thoracic  ganglia  in  the  rabbit.  (From 
Foster's  Physiology.)  Track.  Trachea.  Ca.  Carotid  artery.  Sb.  Subclavian 
artery  n.vag.  Vagus  trunk,  n.  rec.  Recurrent  laryngeal,  sym.  Cervical 
Sympathetic  ending  in  inferior  cervical  ganglia,  gl.  cerv  inf.  Two  roots  of  the 
ganglion  are  shown,  rad.,  the  lower  of  the  two  accompanying  the  vertebral 
artery,  A.  vert,  being  the  one  generally  possessing  accelerator  properties,  ^f^. 
thor.pr.,  the  first  thoracic  ganglion.  Its  two  hranches  communicating  with 
the  cervical  ganglion  surround  the  subclavian  artery  forming  the  annulus  of 
Vieussens.  Sym.  thor.  The  thoracic  sympathetic  chain,  n.  dfp.  Depressor 
nerve.  This  is  joined  in  its  course  by  a  branch  from  the  lower  cervical  gan- 
glion, there  being  a  small  ganglion  at  their  junction,  fiom  which  proceed 
nerves  to  form  a  plexus  over  the  arch  of  the  aorta.  It  is  this  branch  from  the 
lower  cervical  ganglion  which  possesses  accelerator  properties — hence  ths 
course  of  the  accelerator  fibres  is  indicated  in  the  figure  by  the  arrows. 


3.  Accelerator  Nerves. — The  accelerator  nerves 
arise  in  the  medulla  oblongata,  pass  down  the  cervical 
portion  of  the  spinal  cord  and  join  the  last  cervical  and 


ACTION    ON    the;    CIRCULATORY    APPARATUS.      109 

first  dorsal  ganglia,  and  thence  to  the  accelerator  gan- 
glion of  the  heart ;  their  distribution  is  somewhat  different 
in  the  dog  and  the  rabbit.  (See  Figs.  25  and  26.)  Unlike 
the  inhibitory  nerves  of  the  heart,  they  are  not  in  con- 
Fig.  26. 


Diagram  of  the  last  cervical  and  first  thoracic  ganglia  in  the  dog.  (From 
Foster's  Physiology.)  v.  sym.  The  united  vagus  and  cervical  sympathetic 
nerves,  gl.cerv.i.  The  inferior  cervical  ganglion,  n.v.  Continuation  of  trunk 
of  vagus,  ann  V.  The  two  l":iuches  forming  the  annulusof  Vieussens  around 
the  subclavian  artery,  art.  subcl.,  and  joining  gl.  th.pr.,  the  first  thoracic  or 
stellate  ganglion  (the  branch  running  in  front  of  the  artery  is  considered  by 
Schmiedeberg  to  be  an  especial  channel  of  accelerator  fibres).  Sym.  thorac. 
The  sympathetic  trunk  in  the  thorax,  r.  vert.  Communicating  branches  from 
the  cervical  nerves  running  alongside  the  vertebral  artery,  the  rami  verte- 
brales  n.  rec.  The  recurrent  laryngeal,  n.  c.  Cardiac  branches  from  the 
lower  cervical  ganglion,  accelerator  nerves  of  Schmiedeberg.  n'.  c'.  Cardiac 
branch  from  first  thoracic  ganglion,  accelerator  nerves  of  Cyon.  n".  c".  Car- 
diac branch  from  recurrent  nerve,  n.  rec.  Branch  from  lower  cervical  ganglion 
to  the  recurrent  nerve,  often  containing  accelerator  fibres. 


stant  action  ;    hence   their  section    or   paralysis  is  not 
followed  by  slowing  of  the  heart.     Drugs  may  produce 


110  GENERAL    ACTION    OF    POISONS. 

an  increased  rate  of  pulsation  by  direct  stimulation  of 
these  nerves  either  at  their  origin,  in  their  course  or  at 
their  termination  in  the  heart,  or  indirectly  by  producing 
a  diminished  blood-pressure.  The  influence  of  drugs  on 
the  accelerator  apparatus  of  the  heart  has  not  been  as 
thoroughly  worked  out  as  in  the  case  of  the  inhibitory 
mechanisms. 

4.  Va SO-MOTOR  System. — The  normal  tonicity  of  the 
bloodvessels  is  maintainied  by  the  vaso-motor  centre 
located  in  the  floor  of  the  fourth  ventricle  of  the  brain. 

Blood-pressure  may  be  altered  by  drugs  through 
changes  in  the  normal  stimuli  passing  along  the  afferent 
(sensory)  nerves,  changes  in  the  irritability  of  the  vaso- 
motor centre  itself,  or  by  stimulation  or  paralysis  of  the 
efferent  (sympathetic)  nerves.  The  vaso-motor  centre 
may  be  directly  stimulated  by  drugs,  indirectly  through 
the  cervical  sympathetic,  the  vagus  (when  the  brain  is 
intact  and  the  animal  not  narcotized),  or  through  the 
general  sensory  nerves,  when  increased  blood-pressure 
will  rcBult  through  contraction  of  the  abdominal  vessels. 
Previous  section  of  the  splanchnic  nerves  will  prevent 
this  rise  of  blood-pressure.  The  vaso-motor  centre  is 
also  subject  to  irritation  in  changes  in  the  respiratory 
gases  of  the  blood. 

The  vaso-motor  centre  may  also  be  inhibited,  and  de- 
creased blood-pressure  produced,  by  stimulation  of  the 
depressor  nerve. 

The  following  table,  compiled  by  Lauder-Brunton,  is 
introduced  to  facilitate  reference  : — 


ACTION    ON    THE    CIRCULATORY    APPARATUS.      Ill 


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112  GENERAL    ACTION    OF    POISONS. 

After  having  determined  in  tlie  manner  indicated  on 
page  113,  the  general  action  of  the  poison  on  the  circu- 
lation, the  comparative  effects  of  diff"erent  doses  must  be 
studied. 

It  must  also  be  remembered  that  muscular  contractions 
will  cause  an  increased  blood-pressure  ;  hence  when  the 
poison  being  experimented  with  produces  convulsions,  or 
is  a  respiratory  poison,  enough  curare  must  be  given  to 
paralyze  the  motor  nerves  of  the  voluntary  muscles,  and 
artificial  respiration  maintained.  For  this  purpose  an 
ordinary  bellows,  run  at  the  proper  rate  by  a  gas  or 
water  motor,  or  even  by  the  hand,  or  any  of  the  various 
forms  of  air-blasts,  such  as  Sprengel's  air-pump,  may  be 
used  and  the  blast  rendered  intermittent  by  an  electro- 
magnet by  which  a  weight  that  compresses  the  air-tube 
can  be  alternately  elevated  and  depressed. 

In  the  explanation  of  the  results  obtained  in  blood- 
pressure  experiments,  it  will  not  be  necessary  to  here 
give  a  complete  analysis  of  all  the  methods  employed  in 
settling  each  point ;  enough  only  will  be  given  to  show 
the  general  plan  to  be  followed.] 

As  already  said,  the  causes  of  changes  in  the  circula- 
tory mechanism  may  lie  either  in  an  action  of  the  poison 
on  the  muscular  apparatus  of  the  heart,  its  nervous  appa- 
ratus, or  on  the  bloodvessel  system.  The  conditions  which 
modify  the  functional  activity  of  the  cardiac  muscle  can- 
not be  separated  from  those  governing  the  other  muscles 
of  the  body  ;  hence,  general  muscle  poisons,  especially 
those  which  exert  a  paralyzing  influence,  such  as  the  de- 
privation of  the  blood  of  oxygen,  will  act  in  the  same  man- 
ner on  the  heart.  But  since  an  important  part  of  the  car- 
diac nervous  mechanism  is  contained  witliin  the  heart,  it 
is  often  difficult  to  decide  what  effect  should  be  attributed 
to  action  on  the  nervous  system  and  what  to  action  on  the 
muscle.  It  can,  however,  be  positively  stated,  that  a 
poison  acting  on  the  muscular  tissue  of  the  heart  alone, 
may  change  the  force  of  contraction,  but  never  produce 
any  change  in  rhythm;  therefore,  as  a  rule,  it  can  only  be 
held  that  the  poison  acts  on  the  cardiac  muscle  when  it 
produces  progressive  or  total  paralysis  without  change  in 


ACTION    ON    THE    CIRCULATORr    APPARATUS.       113 

rhythm ;  and  the  supposition  is  rendered  more  probable, 
when  the  drug  is  known  to  aifect  other  muscles  in  a  similar 
manner. 

There  is  a  large  group  of  poisons,  of  which  curare  is  a 
good  example,  which  have  no  action  on  the  muscular  ap- 
paratus of  the  heart,  but  which  paralyze  the  nerve  ter- 
minations of  its  motor  apparatus.  The  exact  mode  of 
termination  of  these  nerves  has  not  yet  been  determined 
(?),  but  it  has  been  found  that  these  poisons  only  act  in 
slight  degree,  if  at  all,  on  the  intra-muscular  cardiac 
nerves. 

The  second  and  roost  usual  action  of  a  poison  on  the 
heart  is  on  its  nervous  system. 

[Let  us  suppose  a  case  in  which  the  drug  causes 
quickening  of  the  pulse  ;  by  reference  to  the  table,  we 
see  that  the  heart  may  be  caused  to  beat  more  rapidly 
by  stimulation  of  the  accelerator  nerves  or  ganglia,  either 
directly  or  by  diminished  blood-pressure,  or  by  paralysis 
of  the  inhibitory  nerves  or  ganglia.  If  the  pulse  is  ren- 
dered quick  by  decreased  blood-pressure,  increasing  the 
pressure  by  compression  of  the  aorta,  or  by  an  injection 
of  defibrinated  blood,  should  slow  the  pulse ;  if,  however, 
it  should  happen  that  the  rapid  pulse  is  associated  with 
an  increased  pressure,  this  possibility  of  course  does  not 
exist.  If,  therefore,  we  assume  that  we  are  dealing  with 
a  case  in  which  increased  blood-pressure  is  accompanied 
by  a  rapid  pulse,  the  question  will  be  narrowed  down  as 
to  whether  the  inhibitory  apparatus  of  the  heart  is  para- 
lyzed, or  the  accelerator  apparatus  stimulated.  If  we 
divide  both  pneumogastrics  in  the  neck  before  the  experi- 
ment, and  still  find  that  the  pulse  is  further  increased 
after  the  administration  of  the  drug,  we  can  assume  that 
the  cardio-inhibitory  centre  in  the  medulla  was  not  para- 
lyzed, and  if  we  find  that  the  irritation  of  the  central  end 
of  a  divided  vagus,  the  other  being  intact,  can  reduce 
the  rate  of  pulsation,  we  can  infer  that  the  cause  of  the 
disturbance  does  not  lie  in  the  inhibitory  apparatus. 

Suppose,  however,  we  find  that  the  irritation  of  the 
central  end  of  the  vagus  has  no  effect;  then  the  trouble 

10* 


114  GENERAL    ACTION    OF    POISONS. 

must  lie  either  in  the  vagus  fibres,  in  the  heart  ganglia, 
or  in  the  medullary  ganglion.  The  latter  may  be  par- 
tially excluded  by  the  above  experiment  of  dividing  the 
pneumogastrics  ;  the  question  may  be  still  more  de- 
cisively answered  in  the  following  manner :  It  is  known 
that  after  a  poison  has  been  injected  into  the  circula- 
tion, it  is  only  gradually  distributed  throughout  the  entire 
system,  and  its  characteristic  effects  are  only  produced 
when  the  percentage  of  poison  in  the  blood  reaches 
a  certain  height ;  and  of  course  the  percentage  is  great- 
est at  the  point  of  entrance.  Let  us  now  suppose  that 
we  are  dealing  with  a  case  in  which  either  the  cardiac  or 
medullary  inhibitory  centre  is  either  paralyzed  or  irrita- 
ted; if  we  inject  the  poison  into  the  jugular  vein  towards 
the  heart  and  the  symptoms  (quick  pulse  for  paralysis, 
slow  pulse  for  irritation)  instantly  appear,  the  probabil- 
ity is,  that  the  poison  acts  directly  on  the  heart.  But  if 
some  time,  say  a  minute  or  more,  is  required  before  the 
effects  appear,  the  evidence  then  points  to  implication. of 
the  centres  in  the  medulla,  and  if  we  find  that  injection 
of  the  drug  into  the  carotid  causes  the  instant  appear- 
ance of  the  symptoms,  the  evidence  is  conclusive. 

It  might,  however,  be  necessary  to  determine  whether 
the  vagus  trunks  are  paralyzed  ;  if  the  cardiac  ganglia 
are  intact,  this  can  be  readily  settled  by  testing  whether 
their  irritation  slows  the  heart.  If  the  cardiac  ganglia 
should  be  paralyzed,  the  condition  of  the  vagus  may  still 
be  determined  by  the  presence  or  absence  of  muscular 
contractions  in  the  larynx  after  irritation  of  the  vagus 
above  the  origin  of  the  laryngeal  nerves.  After  paraly- 
sis of  all  portions  of  the  inhibitory  apparatus  are  thus 
excluded,  the  conclusion  can  be  formed  that  the  drug 
acts  by  stimulation  of  the  accelerator  apparatus,  and  this 
can  be  located  in  the  heart,  if  it  should  be  seen  after 
section  of  the  accelerator  nerves. 

The  explanation  of  the  production  of  a  slow  pulse  is 
reached  in  a  somewhat  similar  manner.  Slow  pulse 
from  irritation  of  the  inhibitory  centre  in  the  medulla,  or 
of  the  vagus  trunks,  is  excluded  by  section  of  the  pneu- 


ACTION    ON    THE    CIRCULATORY    APPARATUS.       115 

raogastrics  low  down  in  the  neck,  while  stimulation  of 
the  peripheral  ends  of  the  vagu«  is  rendered  impossible 
by  previously  giving  enough  atropia  to  paralyze  the 
pneumogastrics.  Or  the  comparative  degree  of  excita- 
bility of  the  vagus  trunks  may  be  tested  by  noting  the 
strength  of  current  required  to  slow  the  heart  before 
and  after  the  administration. 

By  methods  similar  to  those  here  outlined,  the  action 
of  a  drug  on  the  extrinsic  cardiac  nervous  system  can  be 
determined  with  tolerable  accuracy  ;  the  study  of  the 
action  of  the  drug  on  the  heart  itself  is,  however,  a 
matter  of  considerably  greater  difficulty.] 

Since  there  are  at  least  three  independent  cardiac 
centres,  viz.,  the  intrinsic  cardiac  centres  and  the  two 
cerebro-spinal  regulating  centres  (the  accelerating  and 
inhibitory  centres),  and  since  all  these  centres  may  be 
influenced  by  the  numerous  nerves  with  which  they  are 
connected,  a  poison  acting  on  the  heart  through  the 
modium  of  the  nervous  system  may  produce  its  charac- 
teristic action  in  several  different  ways  ;  and  the  ques- 
tion is  still  further  complicated  by  the  fact  that  nearly 
all  heart  poisons  act  on  the  heart  in  several  different 
ways  at  the  same  time,  and  the  mode  of  action  may  vary 
in  different  stages  of  poisoning  with  the  same  drug.  The 
following  methods  will  serve  to  give  some  idea  of  the 
course  to  be  followed  in  attempting  an  investigation  of 
these  points. 

The  action  of  the  poison  on  the  ganglia  in  the  heart 
can  be  tolerably  well  isolated  by  allowing  the  poison  to 
act  on  the  excised  frog's  heart,  or  in  mammals  by  sepa- 
rating the  heart  from  the  extrinsic  nervous  system  by 
section  of  all  the  nerves  passing  to  it,  an  extremely 
difficult  operation,^  or  by  division  of  both  pneumogas- 
trics and  sympathetics  in  the  neck  and  the  spinal  cord  be- 
between  the  occiput  and  atlas.  By  either  of  these  meth- 
ods, however,  the  intracardiac  ganglia  are  not  completely 
isolated,    since    there    are    numerous    poisons,    such    as 

^  Ludwig  iind  Thiry,  Wiener  Acad.  Sitzgsber.  1864,  18  Feb. 


116  GENERAL    ACTION    OF    POISONS. 

curare,  nicotine,  atropine,  etc.,  which  produce  their  char- 
acteristic effects  bj  action  on  the  intracardiac  terminal 
fibres  of  the  different  cardiac  nerves,  especially  of  the 
vagus.  In  order  to  establish  a  condition  of  paralysis  of 
these  nerves,  examinations  must  be  made,  before  proceed- 
ing to  the  isolation  of  the  heart,  as  to  whether  irritation 
of  these  nerves  will  produce  the  characteristic  normal  re- 
sult after  the  poison  has  been  given  ;  for  instance,  if  the 
drug  paralyzes  the  intracardiac  endings  of  the  pneumo- 
gastric  nerve,  the  irritation  of  the  nerve  after  the  admin- 
istration of  the  poison  will  fail  to  slow  the  pulse.  To 
determine  whether  the  slowing  of  the  pulse  or  arrest  of 
the  heart,  produced  by  the  poison,  is  due  to  irritation 
of  the  vagus  endings  in  the  heart,  atropia  or  curare, 
which  in  large  doses  are  known  to  paralyze  these  struc- 
tures, is  administered  before  the  drug,  artificial  respira- 
tion kept  up,  and  the  drug  then  given;  in  such  a  case,  if 
the  action  of  the  poison  is  to  slow  the  heart  by  stimula- 
tion of  the  vagus  endings,  the  previous  administratioa  of 
a  drug,  such  as  curare,  which  paralyzes  these  structures, 
will,  of  course,  prevent  the  appearance  of  the  usual 
symptoms. 

After  eliminating  in  this  way,  the  possible  action  of 
the  poison  on  the  termination  of  the  nerves  in  the  heart, 
the  study  of  the  action  of  the  drug  on  the  isolated  heart 
will  then  render  it  possible  to  form  conclusions  as  to  the 
action  on  the  cardiac  gancrlia. 

[From  reasons  already  given,  the  heart  of  the  frog  is 
much  better  suited  for  the  study  of  drugs  than  is  that  of 
the  mammal,  though  recent  improvements  in  the  methods 
of  research  have  rendered  the  heart  of  warm-blooded 
animals  much  more  accessible  for  this  purpose.  The 
methods  of  studying  the  local  action  of  poisons  on  the 
heart  in  situ  have  been  already  given  ;  for  the  excised 
heart,  several  plans  may  be  followed.  The  old  modes  of 
study,  alluded  to  on  page  88,  have  now  been  univer- 
sally supplanted  by  the  methods  of  investigation  intro- 
duced by  Ludwig;  his  plan  was  to  keep  the  heart  sup- 
plied with  serum  and  attached  to  a  manometer,  bv  which 


ACTION    ON    THE    CIRCULATORY    APPARATUS,       ll7 

the  pulsations  of  the  heart  could  be  recorded.  His  origi- 
nal instrument  has  been  considerably  modified  bj  several 
investigators,  and  several  new  forms  of  instruments  for 
this  purpose  are  now  in  use  ;  of  these,  only  two  forms 
will  be  described,  accounts  of  the  others  can  be  found  in 
the  various  physiological  hand-books. 

The  apparatus  used  by  Ludwig  and  Coats  in  their  ex- 
periments on  the  vagus  nerve  is  shown  in  Fig.  27  ;  it  is 

Fig.  27. 


Ludwig  aud  Coats's  frog  maaouieter. 


the  simplest  form  of  frog  manometer,  and  can  be  readily 
extemporized.  It  consists  of  a  manometer  E^  connected 
by  a  canula  B'  with  the  bulbus  aortae  of  a  frog  ;  at  D 
is  another  canula  inserted  into  the  sinus  venosus  and  con- 


118  GENERAL    ACTION    OF    POISONS. 

nected  by  the  tube  Q  with  a  reservoir  A  containino;  di- 
luted rabbit  serum,  or  even  normal  salt  solution.  J^is  a 
heavy  glass  rod,  moving  on  a  sliding  clamp,  for  holding 
the  frog.  The  frog's  heart  is  prepared  by  destroying 
the  brain  and  spinal  cord  and  then  cutting  across  the 
body  below  the  liver  so  as  to  remove  the  lower  extremi- 
ties; the  sternum  and  forelegs  are  then  removed,  leaving 
only  a  flap  of  skin  large  enough  to  cover  the  heart,  which 
is  exposed  in  the  usual  manner ;  one  canula  is  then  in- 
serted in  one  aorta,  pushed  into  the  bulb  and  bound  fast, 
while  the  other  aorta  is  ligated  ;  another  canula  is  then 
inserted  in  the  sinus  venosus.  The  liver  and  lungs  are 
then  removed  and  an  opening  made  in  the  stomach,  and 
the  glass  rod  J  passed  through  the  mouth  and  down 
the  oesophagus ;  the  aortic  canula  is  then  connected 
with  the  manometer  and  the  venous  canula  with  the 
reservoir,  the  stop-cock  B  opened  and  the  serum 
allowed  to  flow  through  the  heart  and  out  at  F^ 
until  all  air  bubbles  are  displaced  and  the  heart  and 
vessels  completely  filled  with  serum.  The  clamp  on  F 
is  then  closed  and  the  pressure  bottle  raised  to  such  a 
height  that  there  is  a  certain  tension  exerted  on  the  heart 
even  during  diastole.  This  method  of  using  this  appa-. 
ratus,  in  which  there  is  no  circulation,  the  serum  simply 
being  forced  out  of  the  ventricle  at  each  systole  and  fall- 
ing back  at  each  diastole,  is  especially  suited  for  the 
study  of  drugs  on  the  vagus  nerve.  The  vagus  is  seen 
in  the  drawing,  and  may  be  readily  found  below  the 
greater  horn  of  the  hyoid  bone  lying  alongside  of  the 
laryngeal  nerve,  which  can  be  readily  recognized  by 
tracing  it  to  its  destination. 

After  normal  tracings  have  been  taken  with  this  ap- 
paratus and  the  eff"ects  of  the  vagus  tested,  some  of  the 
poison  may  then  be  added  to  the  serum  in  the  reservoir 
and  the  results  noted.  In  many  cases,  it  is  better  to 
have  an  active  circulation  through  the  heart,  and  to  be 
able-  to  substitute  normal  for  poisoned  serum.  This 
can  be  readily  accomplished  by  having  two  reservoirs 
standing  on  the  same    level,  the  one  containing  normal 


ACTION    ON    THE    CIRCULATORY    APPARATUS.      119 

serum,  and  the  other  serum  containing  poison  ;  their  flow 
through  the  heart  can  then  be  regulated  by  a  two-waj 
cock,  while  by  opening  slightly  the  clamp  F^  the  serum 
that  is  pumped  through  the  heart  can  be  allowed  to 
escape.  In  the  comparison  of  results  obtained  in  this 
manner  with  normal  and  poisoned  serum,  care  must  be 
taken  that  the  conditions  are  always  uniform ;  that  the 
resistance  at  F^  and  the  pressure  in  the  reservoirs  are 
always  the  same.  By  varying  the  resistance  at  F^  the 
effects  of  increased  or   diminished  capillary  resistance 

Fig.  28. 


Koy's  heart  apparatus. 


may  be  imitated  and  the  effect  of  varying  blood-pressure 
studied  on  the  action  of  the  heart. 

By  means  of  an  instrument  devised  by  Dr.  C.  S.  Rpy^ 

1  Journ.  of  Physiol.,  vol.  i.  No.  6. 


120  GENERAL    ACTION    OF    POISONS. 

the  accurate  study  of  poisons  on  isolated  portions  of  the 
frog's  heart  is  greatly  facilitated.  The  instrument  is 
represented  in  Fig.  28.  The  small  bell-glass  (i?)  rests 
on  a  round  plate  of  brass  (6)  to  which  it  is  fixed  by  the 
aid  of  a  little  stiff  grease.  In  the  upper  opening  of  this 
vessel  is  fitted  a  short  glass  canula,  which  is  perforated 
to  allow  the  passage  of  the  heart  canula ;  inside  this 
canula  is  a  second  tube  of  metal  measuring  about  1  mm. 
in  diameter.  It  extends  from  the  lower  extremity  of  the 
canula  to  a  point  about  5  mm.  from  its  upper  end,  where 
it  passes  through  its  canal,  and  projects  for  a  sufficient 
distance  to  allow  of  an  India-rubber  tube  being  tied  on 
it  (c). 

B}^  means  of  this  canula,  diluted  blood,  or  other  fluid, 
can  be  kept  constantly  circulating  through  the  auricle  or 
ventricle,  which  is  fastened  on  it,  the  rapidity  of  the  flow 
being  regulated  by  the  difference  in  height  of  the  two 
reservoirs  which  are  in  connection  with  the  two  tubes  of 
the  canula. 

In  the  brass  plate  on  which  the  bell-jar  rests  are  two 
openings,  one  of  which  forms  the  inlet  to  a  short  tube  d 
which  is  provided  with  a  stop-cock  e ;  the  other  opening 
is  situated  in  the  centre  of  the  brass  plate  and  forms  the 
inlet  to  a  short  cylinder  closed  below  by  a  non-elastic 
flexible  membrane  to  which  is  attached,  by  a  piston-like 
disk  and  needle,  a  long  light  lever.  The  ventricle,  or 
auricles,  as  the  case  may  be,  having  been  fastened  on, 
and  the  canula  and  reservoirs  filled  with  diluted  blood, 
the  heart  is  introduced  into  the  bell-glass  (which  has 
been  previously  fixed  on  the  plate),  and  its  cavity  filled 
with  olive  oil.  On  now  opening  the  stop-cock  (e)  the 
oil  begins  to  flow  out  through  the  tube  c?,  and  renders  the 
pressure  within  the  bell-glass  sub-atmospheric ;  when 
the  piston  has  thus  been  drawn  up  to  the  point  repre- 
sented in  the  figure  the  stop-cock  is  closed.  With  the 
apparatus  thus  arranged,  each  contraction  of  the  heart 
will  cause  an  elevation  of  the  lever,  and  each  relaxation 
a  fall,  from  the  varying  volume  of  the  contracting  heart. 
Observations  on  the  isolated  ventricle  may  be  made  by 


ACTION    ON    THE    CIRCULATORY    APPARATUS.      121 

cutting  away  the  base  of  the  heart  nearly  down  to  the 
auriculo-vcntricular  sulcus,  inserting  the  canula  into  the 
ventricle  through  one  of  the  auricles  and  then  binding  it 
fast  by  a  ligature  passing  around  the  auricular  wall  near 
the  ariculo-ventrical  groove.  Where  the  ventricle  is 
very  small  the  auricular  septum  may  interfere  with  the 
introduction  of  the  canula ;  in  such  cases  the  auricular 
septum  should  be  slit  through  with  a  pair  of  very  fine 
blunt-pointed  scissors. 

To  fasten  on  the  auricle  to  the  perfusion  canula  the 
lower  two-thirds  of  the  ventricle  is  clipped  off  with  scis- 
sors and  the  auricular  septum  slit  through  with  blunt- 
pointed  scissors,  one  blade  entering  each  auricle  from 
the  ventricular  aspect,  great  care  being  of  course  taken 
to  avoid  cutting  the  walls  of  the  auricles.  The  venae 
cavge  superiores  and  inferior  are  then  ligated,  the  posi- 
tion of  the  ligature  around  the  sinus  venosus  varying  in 
different  experiments ;  the  end  of  the  canula  is  then  in- 
troduced into  the  auricular  cavity  from  the  opened  ven- 
tricle, and  is  fastened  by  a  ligature  passing  around  the 
sulcus,  the  upper  third  of  the  ventricle  or  around  the 
lower  part  of  the  auricular  walls  as  the  case  may  re- 
quire. The  movements  of  the  sinus  venosus  may  also  be 
studied  in  the  same  manner  by  introducing  the  canula  into 
its  cavity.  It  is  seen  that  by  this  method  it  is  rendered 
perfectly  feasible  to  study  the  action  of  poisons  on  each 
separate  portion  of  the  heart ;  tracings  may  first  be  taken 
with  the  organ  supplied  with  diluted  blood  and  then 
with  blood  containing  definite  proportions  of  the  drug. 
It  is  possible  to  experiment  on  the  toxic  changes  which 
the  heart  undergoes  as  regards  its  electric  irritability 
by  using  the  canula  as  one  electrode  and  by  surrounding 
the  canula  where  it  passes  through  the  stopper  with  rub- 
ber, and  outside  of  it  a  sheet  of  tin- foil  whose  projecting 
edge  is  cut  into  a  fringe  ;  outside,  the  tin-foil  is  connected 
with  the  other  pole  of  the  induction  apparatus,  while  in- 
side any  portion  of  the  fringes  may  be  i3laced  in  contact 
with  the  heart  and  serve  as  the  second  electrode. 

The  recent  application  to  the  mammalian  heart  by 
11 


122  GENERAL    ACTION    OF    POISONS. 

Prof.  Martin,^  of  Baltimore,  of  the  Leipzig  method  of 
maintaining  circulation  through  the  organs  of  warm- 
blooded animals  has  rendered  possible  the  study  of  drugs 
on  the  isolated  mammalian  heart.  The  principle  of  this 
method  is  to  prevent  circulation  through  all  parts  of  the 
body  of  a  warm-blooded  animal  but  the  heart  and  lungs ; 
from  want  of  blood,  the  brain,  spinal  cord,  and  sympa- 
thetic ganglia  soon  die,  and  so  the  heart  is  liberated 
from  the  control  of  nerve  centres  outside  of  itself. 

The  animal  being  tracheotomized  and  narcotized,  the 
carotids  are  exposed  and  tied,  and  canulne  placed  in  their 
central  ends ;  the  vagi  are  then  divided  in  the  neck. 
The  next  step  is  to  expose  the  heart  and  great  vessels  by 
resecting  the  front  and  sides  of  the  thorax,  all  bleeding 
vessels  being  ligated.  The  right  and  left  subclavian 
arteries  are  then  tied  below  the  origin  of  their  first 
branches,  thus  cutting  off  nearly  all  blood  from  the  head. 
Next  a  metal  canula,  curved  at  one  end  so  as  to  present 
a  long  limb  and  a  short  limb  at  right  angles  to  one  an- 
other, is  inserted  into  the  aorta  just  above  the  diaphragm 
and  pushed  up  until  its  end  reaches  the  arch,  where  it  is 
bound  fast,  thus  blocking  all  circulation  through  the 
systemic  arteries,  with  the  exception  of  the  coronaries. 
The  next  step  is  to  tie  the  systemic  veins  leading  to  the 
right  auricle ;  a  ligature  is  placed  around  the  inferior 
vena  cava  above  the  diaphragm,  another  around  the  vena 
azygos  near  its  entry  into  the  superior  vena  cava,  and 
the  latter  is  then  ligated  on  the  cardiac  side  of  its  last 
tributary.  On  the  cardiac  side  of  this  ligature  a  large 
tube,  in  communication  with  a  flask  containing  defibri- 
nated  diluted  blood,  is  introduced,  the  carotids  opened, 
and  all  the  blood  previously  present  in  the  heart  and 
lungs  displaced  by  defibrinated  blood.  A  thermometer 
being  inserted  in  the  left  carotid,  and  the  right  connected 
with  the  manometer  tube,  the  animal  is  then  transferred 
to  a  warm  moist  chamber. 

1  Trans,  of  the  Med.  and  Chir.  Fac.  of  Maryland,  April,  1882, 
p.  203. 


ACTION    ON    THE    CIRCULATORY    APPARATUS.       123 


The  aortic  canula  is  connected  with  a  long  rubber 
tube  having  at  its  distal  end  a  bent  glass  tube  from 
which  the  blood,  forced  out  by  each  contraction  of  the 
left  ventricle,  is  poured  into  a  funnel ;  from  this  funnel 
a  tube  leads  to  a  Mariotte's  flask  exactly  like  that  in 
connection  with  the  right  auricle.  The  blood  taken 
by  the  right  heart  under  definite  pressure  from  one 
Mariotte's  flask  is  thus  pumped  into  another,  from  which, 
by  changing  a  couple  of  stop-cocks,  it  can  a  second  time 
flow  into  the  right  heart.  Varying  blood-pressure  can 
be  produced  by  elevating  or  depressing  the  end  of  the 
aortic  exit-tube,  while  the  addition  of  the  poison  to  the 
blood  in  the  venous  reservoir  will  enable  its  action  on 
the  isolated  heart  to  be  studied. 

In  the  attempt  to  localize  the  action  of  heart  poisons 
on  different  portions  of  the  ganglionic  apparatus  of  the 
heart,  one  of  two  ways  may  be  followed,  though  neither 
in  the  present  state  of  cardiac  physiology  deserves  to 
be  designated  as  a  method.  Either  the  poison  may  be 
administered  to  pulsating  fragments  of  the  frog's  heart 
by  means  of  Roy's  apparatus,  and  some  conclusion 
attempted  from  the  known  anatomical  peculiarities  of 
the  part,  or  the  method  of  antago- 
nisms may  be  followed.  In  gen- 
eral, the  latter,  although  it  is  true 
that  its  data  are  largely  based  on 
assumptions,  will  lead  to  the  most 
reliable  results.  Thus  in  the  dia- 
gram. Fig.  29,  the  fibres  repre- 
sented by  the  dotted  line  A,  are 
said  to  be  paralyzed  by  nicotine, 
the  ganglion  i  irritated  by  mus- 
carine, and  the  fibres  B  paralyzed 
by  atropine.  Suppose,  therefore, 
we -find  that  a  drug  produces  in- 
creased rapidity  of  the  pulse  in 
an  excised  or  isolated  heart ;  we 
may  first  irritate  the  vagus,  we  find  it  fails  to  slow  the 
pulse  ;   we  then  irritate  the  sinus  venosus,  still   without 


Fig.  29. 


Diagram  of  the  hypotheti- 
cal nervous  apparatus  of  the 
heart. 


124  GENERAL    ACTION    OF    POISONS. 

effect ;  we  then  add  a  few  drops  of  muscarine  and  still 
find  that  the  heart  is  not  slowed.  We  then  know  that 
the  fibres  b  must  be  paralyzed  by  the  drug  in  question. 
Or  suppose  a  case  in  which  muscarine  could  slow  the 
pulse,  while  irritation  of  the  vagus  failed  ;  w^e  then  know 
that  the  fibres  A  were  paralyzed.  If  the  drug  should 
slow  the  pulse,  and  the  subsequent  administration  of 
nicoline  should  not  restore  the  normal  rate,  we  would 
suppose  that  some  portion  of  the  ganglionic  apparatus 
nearer  the  motor  centre  than  a  must  be  affected,  and 
if  we  found  that  atropine  would  remove  the  effect  of  the 
drug,  it  would  be  probable  that  the  drug  in  question 
produced  slowing  of  the  pulse  by  stimulation  of  the  in- 
hibitory ganglion  I. 

As  regards  the  action  on  the  accelerator  apparatus 
our  knowledge  is  not  so  complete.  When  we  find  that 
a  drug  quickens  the  excised  heart,  we  have  one  of  two 
possibilities  to  consider ;  either  the  paralysis  of  the  in- 
hibitory  apparatus  or  the  stimulation  of  the  accelerator 
apparatus.  The  former  may  be  excluded  by  previous 
paralysis  of  the  inhibitory  ganglia  by  atropia.  If  now 
the  drug  produces  quickening  we  know  that  it  must  be 
by  action  on  the  accelerator  apparatus  ;  further  than  this 
we  cannot  at  present  go,  as  the  list  of  drugs  which  act 
on  the  accelerator  ganglia  is  very  limited  and  not  yet 
well  worked  out.] 

The  third  cause  of  modifications  in  the  action  of  the 
heart  and  in  blood-pressure  produced  by  a  poison,  lies  in 
the  condition  of  the  peripheral  vascular  system.  The 
degree  of  contraction  of  the  bloodvessels,  particularly  of 
the  arteries,  not  only  influences  the  degree  of  blood-pres- 
sure in  the  vessels,  but  also  the  frequence  and  energy  of 
the  heart's  contractions.  Thus,  by  ligation  of  any  large 
arterial  trunk,  such  as  the  descending  aorta,  the  pressure 
in  all  the  other  arteries  and  in  the  left  side  of  the  heart 
can  be  so  increased  that  the  distended  heart  will  be  only 
able  to  perform  very  feeble  contractions.  It  has  also 
been  experimentally  determined  that  the  calibre  of  the 
smaller  arteries  is   subject  to  variation  depending  upon 


ACTION    ON    THE    CrRCULATORY    APPARATUS.      125 

the  degree  of  contraction  of  their  muscular  walls,  and 
that  this  contractility  is  governed  by  the  impulses  coming, 
by  the  efferent  vaso-motor  nerves,  from  the  principal  vaso- 
motor centre  in  the  medulla  ^ 

Many  poisons  influence  the  degree  of  arterial  con- 
traction either  by  direct  action  on  the  arteries  (either  by 
action  on  their  muscular  fibres  or  on  the  hypothetical 
peripheral  vaso-motor  ganglia),  or  on  the  vaso-motor 
centre  in  the  medulla,  so  as  to  produce  either  paralysis 
and  dilation  of  the  arteries  with  a  consequent  reduced 
blood-pressure,  or  a  reduction  in  calibre  with  a  conse- 
quent great  increase  in  blood  tension.  Experiment  has 
further  shown  that  each  increase  in  pressure  is  usually 
accompanied  by  a  reduction  in  the  pulse,  and  each  reduc- 
tion in  pressure  by  an  increase  in  the  pulse.^ 

It  is,  therefore,  unwarrantable  to  form  any  conclusion 
as  to  the  cause  of  modifications  in  the  heart's  action 
until  the  possible  reflected  influence  of  changes  in  the 
conditions  of  the  bloodvessels  has  been  considered.  The 
reflex  influence  of  the  central  vaso-motor  centre  on  the 
heart  can  be  eliminated,  without  interfering  with  the 
activity  of  the  accelerating  nerves,  by  section  of  the 
spinal  cord  on  the  level  of  the  second  dorsaP  vertebra, 
or  by  division  of  the  splanchnic  nerves.*  But  even 
with  this  procedure  the  possibility  of  direct  toxic  action 
on  the  muscular  fibres  of  the  arteries  still  remains. 
Observations  as  to  the  condition  of  the  bloodvessels  arc 
most  readily  made  on  the  ear  of  the  rabbit,  especially 
after  depilation  with  sulphide  of  calcium,^  in  the  wing 
of  the  bat,  or  in  the  retinal  vessels  of  all  animals  capa- 
ble of  being  examined  with  the  ophthalmoscope  ;  the 
mesentery  or  swimming  bladder  of  the  frog  can  also  be 
used  for  the  same  purpose. 

^  For  the  exact  location  of  this  centre  see  Owsjannikow,  Sach. 
Acad.  Ber.  1871,  p.  135. 

2  See  Ludwig  and  Thiry,  Wiener  Acad.  Sitzgsber.,  1864,  Feb.  18. 

3  V.  Bezold,  Untersuch.  aus  d.   physiol.  Lab.  in  Wiirzburg,  2 
Heft,  1867. 

4  See  M.  and  E.  Cyon,  Arch.  f.  Anat.  u.  Physiol.,  1867,  p.  395. 
*  See  Samuel,  in  Moleschott's  Untersuch.,  ix.  p.  654. 

11* 


126  GENERAL    ACTION    OF    POISONS. 

[Exclusive,  then,  of  modifications  dependent  directly 
upon  the  heart,  the  blood-pressure  may  be  modified  by 
the  direct  action  of  the  drug  on  the  afterent  vaso-motor 
nerves,  on  the  vaso-motor  centre  in  the  medulla  (and 
cord?)  and  on  the  efferent  nerves.  Consequently,  when 
it  is  found  that  a  drug  produces  a  reduction  in  blood- 
pressure,  after  the  exclusion  of  the  causes  depending  on 
cardiac  action,  the  condition  may  be  due  to  paralysis  of 
the  vaso-motor  centre  from  direct  action  of  the  drug,  to 
paralysis  of  the  afierent  or  efferent  vaso-motor  nerves,  to 
irritation  of  the  depressor  nerve,  or  to  direct  local  action 
on  the  bloodvessels. 

When  the  cause  has  been  located  in  the  vaso-motor 
apparatus,  the  precise  seat  of  the  paralysis  can  only  be 
determined  by  working  from  the  periphery  to  the  centre  ; 
thus  the  normal,  or  abnormal,  condition  of  the  arterial 
walls  must  be  first  determined,  then  that  of  the  efferent 
vaso-motor  nerves,  then  tlie  vaso-motor  centre,  and  finally 
that  of  the  afferent  vaso-motor  nerves.  In  most  cases  it 
is  extremely  difficult  to  separate  direct  toxic  action  on 
the  bloodvessels  from  action  on  the  efferent  vaso-motor 
nerves,  though  some  deductions  may  be  drawn  from  the 
characters  of  the  circulation  in  excised  organs ;  the 
methods  for  carrying  on  these  studies  will  be  given  under 
their  appropriate  heads. 

If  the  poison  produces  reduced  blood-pressure  from 
direct  action  on  the  vascular  walls,  whether  on  their 
nerve-ending  or  muscular  fibres,  we  would  expect  that 
after  arterial  tension  has  been  reduced  through  section 
of  the  cord,  and  the  influence  of  the  vaso-motor  centre 
thus  eliminated,  the  administration  of  the  drug  would  be 
followed  by  a  still  more  marked  fall  in  pressure. 

Local  action  on  the  bloodvessels  may  be  excluded,  as 
was  done  by  Filehne  in  the  case  of  nitrite  of  amyl,  by 
maintaining  artificial  circulation  with  normal  blood 
through  the  vessels  of  the  external  ear  of  a  rabbit,  and 
then  administering  the  poison  either  by  injection  into  the 
venous  system  at  large,  or  through  the  trachea  when  in 
the  form  of  a  vapor.     Should  the  vessels  then  dilate, 


ACTION    ON    THE    CIRCULATORY    APPARATUS.      127 

local  action  on  their  walls  or  on  the  nerve  endings  would 
be  excluded. 

Another  method,  also  employed  by  Filehne  for  the 
same  purpose,  is  to  maintain  a  condition  of  moderate 
contraction  of  the  auricular  vessels  by  stimulation  of  the 
cervical  sympathetic  on  one  side  with  a  weak  interrupted 
current ;  if  dilatation  should  not  appear  on  that  side  after 
administration  of  the  drug,  but  exist  on  the  ear  of  the 
opposite  side,  the  dilatation  could  be  attributed  to  dir 
minished  tonus  of  the  vaso-motor  centre. 

The  irritability  of  the  efterent  vaso-motor  nerves  may 
be  determined  by  irritating  the  dorsal  spinal  cord,  or  the 
splanchnic  nerves,  when,  if  the  efferent  vaso-motor  fibres 
preserve  their  functions,  the  blood-pressure  will  be  greatly 
increased  from  contraction  of  the  abdominal  arterioles  ; 
should  they  or  the  arterial  walls  be  paralyzed,  no  such 
rise  will  be  produced.  Or  the  central  end  of  the  divided 
cervical  sympathetic  may  be  stimulated  in  a  rabbit  and 
the  auricular  vessels  directly  inspected;  should  they  con- 
tract, it  will  be  evident  that  the  vaso-motor  paralysis  is 
located  in  the  centre  or  in  the  afferent  nerves. 

The  irritability  of  the  vaso-motor  centre  may  be  de- 
termined by  screwing  one  gimblet  electrode  into  the 
occipital  bone  and  the  other  into  the  atlas,  until  their 
points  penetrate  the  neural  cavity,  and  passing  an  in- 
duced current  through  them.  Or  the  vaso-motor  centre 
may  be  irritated  by  compressing  the  carotid  arteries  in 
the  neck  by  raising  them  on  threads  ;  in  a  normal  con- 
dition this  experiment  produces  an  increase  in  blood- 
pressure.  If  the  blood-pressure  is  increased  by  eithar 
of  these  modes  of  stimulation,  it  may  be  considered  de- 
monstrated that  the  vaso-motor  centre  and  efferent  nerves 
preserve  their  functions,  and  it  will  then  be  necessary 
to  determine  the  condition  as  regards  the  power  of  trans- 
mitting impression  possessed  by  the  afferent  vaso-motor 
nerves.  This  is  accomplished  by  irritating  the  central 
end  of  the  divided  sciatic  nerve,  a  procedure  which 
normally  is  followed  by  an  increase  in  blood-pressure. 

Should  all  these  experiments  demonstrate  a  normal 


128  GENERAL    ACTION    OF    POISONS. 

state  of  irritability  of  the  vaso-motor  apparatus,  atten- 
tion must  then  be  directed  to  the  depressor  nerve.  This 
nerve,  which  is  a  branch  of  the  pneumogastric  nerve,  or 
rather  a  root  of  the  latter,  which  in  the  rabbit  joins  it  at 
the  level  of  the  superior  laryngeal  nerves,  possesses  the 
power  through  its  irritation  of  inhibiting  the  vaso-motor 
centre  in  the  medulla  and  thus  producing  a  marked  fall 
in  blood-pressure.  If,  therefore,  both  these  nerves  are 
cut  in  the  rabbit  before  the  administration  of  the  poison 
the  possibility  of  their  influence  in  the  production  of 
reduced  blood-pressure  will  be  excluded. 

It  should,  moreover,  be  always  remembered  that  drugs 
which  produce  paralysis  of  the  vaso-motor  system  usually, 
especially  with  small  doses,  first  cause  a  condition  of 
irritation  of  this  apparatus,  hence  the  fall  of  blood-pres- 
sure is  generally  preceded  by  an  initial  rise.] 

Indirect  Results  of  Circulatory  Disturbances. — 
In  cold-blooded  animals  marked  disorders  of  the  circu- 
latory apparatus  are  without  effect  on  other  functional 
activities  ;  it  is  only  when  they  are  long  continued  that 
general  disturbances  appear,  and  after  a  time,  after  com- 
plete arrest  of  the  heart,  the  animal  gradually  becomes 
more  and  more  sluggish,  its  loss  of  power  gradually  pass- 
ing into  complete  paralysis  and  death. ^  The  secondary 
cause  of  these  disturbances,  after  arrest  of  the  circula- 
tion, probably  lies  in  increasing  deprivation  of  oxygen 
affecting  the  central  nervous  system  and  muscles  simul- 
taneously. Increased  rapidity  of  heart  pulsation  is 
entirely  without  effect. 

In  warm-blooded  animals,  on  account  of  their  constant 
need  of  fresh  supplies  of  oxygen,  every  considerable  re- 
duction in  the  rate  of  the  heart's  beats,  and  especially 
arrest  of  the  heart,  is  accompanied  immediately  by  the 
gravest  general  disturbances,  and  the  recognition  of  this 
interdependence  of  general  functional  activities  and  the 
state  of  the  circulation,  first  pointed  out  by  Rosenthal,^ 

'  [See  in  this  connection  Ringer  and  Murrell,  Journ.  of  PhysioL, 
vol.  i.  No.  1.  p.  72.] 

«  Arch.  f.  Anat.  u.  Phvsiol.,  18l)5.  COl. 


ACTION    ON    THE    CIRCULATORY    APPARATUS.       129 

is  to  be  regarded  as  one  of  the  most  important  advances 
in  scientific  pharmacology. 

Arrest  of  the  heart  causes  a  complete  stagnation  of 
the  blood  in  all  the  vessels,  and  as  a  consequence  we  have 
on  the  one  side,  a  cessation  of  absorption  of  oxygen  from 
arrested  pulmonary  circulation,  and  on  the  other  side, 
the  different  organs  are  supplied  with  a  diminished  quan- 
tity of  blood  which  rapidly  gives  up  its  oxygen  and  be- 
comes loaded  with  carbonic  acid.  This  interruption  in 
the  oxygenation  of  the  blood  in  warm-blooded  animals 
rapidly  destroys  the  functions  of  all  organs  and  soon 
leads  to  general  systemic  death.  Before,  however,  death 
occurs,  there  appears  a  series  of  phenomena  depending 
upon  the  arrested  circulation  in  the  medulla  oblongata. 
At  first  the  respiratory  centre  is  abnormally  stimulated 
by  the  altered  cliaracter  of  the  blood,  and  when  the 
venosity  of  the  blood  passes  a  certain  degree,  the  stimu- 
lation extends  to  the  neio-hborinsi;  motor  and  vaso-motor 

CD  O 

centres  in  the  medulla,  and  contraction  of  all  the  small 
arteries,  and  then  general  convulsions  follow.  Hence, 
arrest  of  the  heart  is  followed  by  the  same  train  of 
symptoms  as  interruption  of  the  circulation  in  the  brain 
by  ligation  of  the  cerebral  arteries  or  veins  (which  pro- 
duced the  same  arrest  of  cerebral  circulation  as  stoppage 
of  the  heart),  or  as  interference  with  respiration ;  namely, 
in  the  first  place,  increasing  vigor  of  respiration  up  to 
dyspnoia,  then  general  convulsions  and  arterial  spasm, 
while  the  phenomena  of  asphyxia  first  make  their  appear- 
ance when  the  amount  of  oxygen  in  the  blood  of  the 
medulla  oblongata  has  fallen  so  low  that  the  nerve  centres 
lose  their  irritability.  These  phenomena  will  be  more 
closely-  studied  under  the  respiratory  changes  produced 
by  poisons. 

It  consequently  follows  from  what  has  been  said  that 
arrest  of  the  heart,  or  even  every  considerable  reduc- 
tion in  the  heart's  activity,  must  in  warm  blooded  ani- 
mals cause  dyspnoea,  general  convulsions  and  asphyxia. 
When  therefore  a  poison  causes  convulsions  in  warm- 
blooded animals  and  not  in   frogs,  it  must  always  be 


130  GENERAL    ACTION    OP    POISONS. 

determined  whether  the  drug  does  not  in  the  first  place 
cause  stoppage  of  the  heart. 

In  this  way  other  nerve  centres,  especially  those 
governing  the  movements  of  the  intestine,'  and  con- 
tractions of  the  uterus,^  are  influenced  like  the  respir- 
atory and  vaso-motor  centres  by  increased  venosity  of  the 
blood,  and  consequently  increased  intestinal  peristalsis 
and  uterine  contractions  may  be  results  of  interference 
with  the  circulation. 

The  consequences  of  less  grave  circulatory  disturb- 
ance are  to  be  explained  as  depending  upon  alterations 
of  blood-pressure  (see  p.  91).  Nearly  all  functions  are 
intimately  dependent  upon  the  degree  of  blood-tension 
in  the  organ  with  which  they  are  associated,  and  there- 
fore every  marked  change  from  the  normal  blood-press- 
ure, through  toxic  action  on  the  heart  or  bloodvessel 
system,  soon  leads  to  functional  disorders.^  The  most 
marked  and  the  earliest  of  these  disorders  occur  in  the 
functions  of  the  cerebrum,  where  diminished  blood- 
pressure  leads  to  dizziness  and  syncope,  and  increased 
pressure  to  sense  disturbances,  delirium  and  loss  of  con- 
sciousness. 


Section  II . — Action  on  the  Respiratory  Apparatus. 

A  general  idea  as  to  the  condition  of  the  respiratory 
apparatus  may  be  gained  by  mere  inspections  of  the  tho- 
rax. A  greater  degree  of  accuracy  is  attainable  when 
inspection  of  the  diaphragm  is  rendered  possible  by  open- 
ing the  abdomen  ;  or,  without  opening  the  abdominal 
cavity,  by  the  insertion  of  a  long  needle  through  the 
body  walls  into  the  diaphragm.     In  order  to  reproduce 

•  Mayer  u.  von  Basch,  Wiener  Med.  Jahrbiiclier,  1872. 

*  Oser  u.  Schlesinger,  Weiner  Med.  Jahrbiiclier,  1872. 

'  The  best  statement  of  these  facts  is  to  be  found  in  a  lecture  by 
Ludvvig,  Die  Phvsiologischen  Leistungen  des  Blutdruckes,  Leipzig, 
18t)5. 


ACTION    ON    THE    RESPIRATORY    APPARATUS.       131 

the  respiratory  movements  graphically  Rosenthal's 
phrenograph  or  Marey's  pneumograph  may  be  used. 

In  certain  cases  it  is  necessary  to  determine  the 
volume  of  the  respiratory  movements  ;  for  this  purpose 
Hutchinson's  spirometer  or  an  ordinary  gas-meter,  con- 
nected with  the  trachea,  may  be  employed. 

[The  changes  in  the  frequency  and  rhythm  of  the  re- 
spiratory movements  may  be  graphically  represented  by 
means  of  Marey's  tambour,  either  arranged  as  in  the  figure 
(Fig.  30)  or  by  connecting  the  tube  d  directly  with  the 
tracheal  canula,  which  must  then  be  provided  with  an 
opening  at  one  side  to  enable  the  animal  to  obtain  fresh 
air. 

KnolP  recommends  the  insertion  of  the  animal  in  a  box 
which  can  be  closed  air-tight,  the  trachea  of  the  ani- 
mal being  connected  with  the  exterior  by  a  tube  pass- 
ing through  the  top  of  the  box,  while  the  respiratory 
movements  are  recorded  by  connecting  the  interior  of  the 
box  by  a  tube  with  a  Marey's  polygraph.] 

a.  Dyspncea. — The  most  frequently  observed  effect  of 
poisons  on  the  respiratory  apparatus  is  dyspnoea,  made 
evident  by  an  increased  vigor  of  the  respiratory  move- 
ments and  action  of  the  accessory  muscles  of  respira- 
tion ;  usually,  the  frequency  of  the  respiratory  move- 
ments is  also  diminished. 

The  cause  of  dyspnoea  is  invariably  an  irritation  of  the 
respiratory  centre  in  the  medulla  oblongata  ;  this  irrita- 
tion is  always  to  be  found  in  the  blood  which  acts  as  an 
excitant  to  the  respiratory  centre  in  proportion  as  it  be- 
comes poorer  in  oxygen  and  richer  in  carbon  dioxide.^ 
These  morbid  states  of  the  blood,  which  are  therefore 
the  final  cause  of  dyspnoea,  can  exist  either  in  the  blood- 
vessels of  the  medulla  or  the  head,  as  has  already  been 

1  Sitzber.  der  Akad.  zu  Wein.,  3  Abth.  Bd.  Ixviii.  s.  245. 

2  These  alterations  of  the  blood  are  mutually  interdependent ; 
the  question  as  to  whicli  of  the  two  conditions  is  the  true  excitant 
still  remains  undecided. 


132 


GENERAL    ACTION    OF    POISONS. 


ACTION    ON    THE    RESPIRATORY    APPARATUS.      133 

mentioned  on  p.  128,  or  they  may  prevail  in  the  blood  at 
large  ;  this  latter  condition  is  the  more  usual. 

The  reduction  in  percentage  of  oxygen  in  the  blood 
and  the  excess  of  carbon  dioxide,  or,  as  Hering  terms  it, 
the  increased  venosity  of  the  blood,  may  be  due  to  any 
or  all  of  the  following  conditions :  1 .  Diminished  or 
retarded  absorption  of  oxygen  in  respiration.  2.  Di- 
minished exhalation  of  carbon  dioxide  in  respiration.  3. 
Expulsion  or  abnormal  consumption  of  the  oxygen  origi- 
nally in  the  blood.  4.  Abnormal  absorption  of  carbon 
dioxide. 

The  first  two  of  these  conditions  are  ordinarily  pro- 
duced by  interference  with  the  respiratory  movements, 
and  may  be  produced  by  poisons  through  paralysis  of 
the  respiratory  apparatus,  either  of  the  respiratory 
centre,  nerves  or  muscles.  In  this  case,  however,  to 
produce  dyspncea^  the  paralysis  must  be  confined  to 
individual  respiratory  muscles  ;  or  they  may  be  due  to 
interference  with  the  pulmonary  circulation  (see  heart 
paralysis,  p.  129),  or  finally,  to  inability  for  absorption 
of  oxygen  by  the  blood.  This  latter  cause,  with  the 
exception  of  dyspnoea  produced  by  heart-poisoning,  is  the 
most  frequent  factor  in  the  toxic  production  of  respiratory 
difficulties.  The  blood  can  be  unfitted  for  absorbing 
oxygen  either  through  alteration  of  the  haemoglobin,  or 
through  destruction  of  the  red  corpuscles. 

The  third  of  the  above  mentioned  conditions  which  may 
act  as  causes  of  dyspnoea,  the  expulsion  of  the  oxygen 
from  the  blood,  can  naturally  only  exist  as  such  when 
it  is  produced  so  rapidly  that  the  lost  oxygen  cannot  be 
replaced  with  sufficient  rapidity,  to  preserve  a  normal 
proportion,  by  the  fresh  oxygen  taken  in  respiration,  or 
when  the  blood  is  at  the  same  time  and  by  means  of  the 
same  agent  unfitted  for  absorption.  Sulphuretted  hydro- 
gen is  an  example  of  a  poison  which  produces  the  first 
of  these  conditions,  carbon  mon-oxide,  of  the  second. 

The  fourth  condition  may  occur  when  an  atmosphere 
abnormally  contaminated  with  carbon  di-oxideis  inspired. 

If,  now,  this  poverty  of  oxygen  and  richness  in  carbon 
12 


134  GENERAL    ACTION    OF    POISONS. 

di-oxide  of  the  blood  continues,  the  dyspnoea  passes  into 
general  convulsions  as  the  increasing  irritation  extends 
to  other  centres  in  the  medulla.  Should  the  deprivation 
of  oxjgen  still  advance,  the  irritability  of  both  the  nerve 
centres  and  the  muscles  gradually  fails,  the  convulsions 
cease,  and  are  replaced  by  asphyxia,  which  is  not  death 
so  long  as  the  heart  continues  to  beat  and  still  possesses 
the  poAver,  through  introduction  of  oxygen  into  the  blood, 
of  bringing  the  organism  back  to  its  normal  condition. 
Should  this  occur,  as,  for  example,  through  artificial  res- 
piration, the  irritability  of  the  nerve  centres  is  first  re- 
newed, and  convulsions  are  again  produced  ;  the  rapid 
disappearance  of  the  irritation  soon  causes  the  convulsions 
to  be  replaced  by  dyspnoea  and  this  finally  gives  place  to 
normal  respiration.  The  consequences  of  dyspnoea  can- 
not be  specified,  since  dyspnoea  is  essentially  a  compen- 
satory process,  tending  to  remove  the  abnormal  condition 
of  the  blood  through  increased  absorption  of  oxygen  and 
exhalation  of  carbon  di-oxide  by  deeper  breathing. 

h.  Cessation  of  Respiratory  Movements. — Besides 
dyspnoea,  poisons  may  produce  weaker  respiratory  move- 
ments or  cause  their  complete  suppression.  The  causes 
of  these  conditions  may,  in  general,  be  either:  — 

1.  Reduction  of  the  Respiratory  Stimulus  through 

SATURATION  OF  THE  BlOOD  WITH  OXYGEN  AND  DIMINU- 
TION IN  ITS  Carbon  Di-oxide. — This  condition,  which 
can  scarcely  be  regarded  astoxicological,is  termed  apnosa, 
and  may  be  produced  by  vigorous  artificial  respiration  ; 
it  is  made  use  of  experimentally  when  it  is  desired  to 
study  successive  stages  of  the  general  action  of  a  drug 
whose  administration  is  otherwise  followed  by  dyspnoea. 

2.  Reduction  in  Irritability  of  the  Respiratory 
Centre. — This  condition  may  be  the  result  of  either 
a  direct  action  of  the  poison,  or  the  consequence  of  such 
a  reduction  in  the  amount  of  oxygen  in  the  blood  that  the 
nerve  centres  are  no  longer  irritable,  a  condition  which 
always  occurs  in  the  last  stage  of  dyspnoea  (see  asphyxia, 
above).    It  is  directly  productive  of  death,  since  not  only 


ACTION    ON    THE    RESPIRATORY    APPARATUS.      135 

the  respiratory  centre,  but  all  the  other  centres,  especi- 
ally those  of  the  heart,  become  simultaneously  paralyzed 
either  from  the  same  cause  or  from  the  cessation  of  res- 
piration. If  the  asphyxia  is  the  result  of  a  direct  action 
of  the  poison  on  the  respiratory  centre,  the  activity  of 
the  heart,  and  therefore  life,  can  be  preserved  by  artifi- 
cial respiration.  If,  on  the  other  hand,  the  asphyxia  is 
due  to  an  absence  of  oxygen  in  the  blood,  artificial  respi- 
ration will  only  prove  effective  when  mere  increased 
access  of  oxygen  will  serve  to  supply  the  deficiency. 

[Respiratory  changes  may  be  referred  to  direct  action 
of  the  drug  on  the  respiratory  nerve  centre  when  they 
occur  after  section  of  the  vagi,  and  after  the  influence  of 
circulatory  changes  has  been  excluded.  This  point  may 
be  determined  by  injecting  the  drug  into  the  carotid 
artery  toward  the  brain,  while  a  blood-pressure  observa- 
tion is  made  in  the  crural  artery  ;  if  respiratory  changes 
occur  before  any  disturbance  of  the  circulation,  the  latter 
may  be  excluded  as  the  active  cause.  Of  course  the  possi- 
bility of  the  effects  of  the  drug  being  due  to  alterations 
in  the  blood  or  its  gases  must  be  taken  into  consideration.] 

3.  Paralysis  of  the  Respiratory  Muscles.— This 
condition  will  be  produced  by  drugs  producing  general 
paralysis,  e.  g.,  curare.  Death  results  from  deficiency 
in  absorption  of  oxygen,  ordinarily  without  preliminary 
dyspnoea  or  convulsions  ;  in  such  circumstances  life  may 
be  preserved  by  artificial  respiration. 

c.  Alterations  in  the  Frequency  of  the  Respira- 
tory Movements  — The  rate  of  respiratory  movement 
is  dependent  upon  the  rhythmical  functions  of  the  respi- 
ratory centre,  upon  the  condition  of  excitation  of  the 
regulating  nerves,  especially  those  running  in  the  pneu- 
mogastric,  and  upon  mental  or  cerebral  stimuli.  Drugs 
may  change  the  rate  of  respiration  through  any  one  of 
these  paths :  ordinarily  the  modus  operandi  may  be  ac- 
curately enough  determined. 

Cerebral  or  mental  sources  of  stimuli  on  the  respira- 
tory centre  may  readily  be  established  in  man,  and  in 


136  GENERAL    ACTION    OF    POISONS. 

animals  they  may  be  excluded  through  previous  narcoti- 
zation or  extirpation  of  the  cerebral  cortex. 

Irritation  of  the  regulator  nerves,  at  least  when  start- 
ing  from  their  peripheral  terminations,  may  be  eliminated 
by  section  of  the  nerve  trunks. 

Changes  in  frequency  persisting  after  exclusion  of  the 
two  preceding  modes  of  action  must  depend  upon  the 
direct  action  of  the  poison  on  the  respiratory  centre. 

Changes  in  the  rate  of  respiration  must  be  very 
marked  to  produce  any  evident  general  results.  It 
should,  however,  be  remembered  that  slowing  of  the  res- 
piration may  be  an  introductory  symptom  of  complete 
cessation  of  respiration,  increased  respiration,  of  tetanus. 

In  both  cases  the  consequences  will  be  the  same,  in  a 
general  way,  as  those  which  follow  complete  cessation 
of  respiration. 

d.  Appearances  in  the  Larynx. — Poisons  may  affect 
either  the  sensory  or  motor  functions'  of  the  larynx. 
Insensibility  of  the  larynx,  ordinarily  only  one  sign  of 
more  general  anaesthesia,  interferes  with  the  normal  pro- 
tective influence  exerted  by  the  larynx  over  the  lungs 
by  the  absence  of  the  possibility  of  reflex  closure  of  the 
glottis  ;  a  similar  danger  may  also  be  produced  in  paral- 
ysis of  either  the  laryngeal  nerves  or  muscles. 

On  the  other  hand,  poisons  may  cause  spasm  of  the 
glottis,  and  so  interfere  with  normal  respiration,  either 
reflexly  by  irritation  of  the  sensory  nerves,  as  in  inhala- 
tion of  irritating  gases  and  vapors,  or  by  direct  action  on 
the  nerve  centres  or  muscles. 


Section  III. — Action  on  the  Digestive  Apparatus. 

Under  this  head,  which  has  been  less  studied,  and  is, 
therefore,  more  obscure  than  any  other  branch  of  phar- 
macology, distinction  must  be  made  between  changes  in 
the  movements  of  the  digestive  organs,  the  production  of 


ACTION    ON    THE    DIGESTIVE    APPARATUS.      137 

abnormal  sensations,  alterations  in  the  secretions,  and, 
finally,  changes  in  the  digestive  processes. 

a.  Alterations  in  the  Movements  of  the  Diges- 
tive Organs. — 1.  Movements  of  the  Jaws.  The  only 
toxic  eftect  evidenced  by  movements  of  the  jaws  [except 
the  masticatory  movements  which  follow  the  introduction 
of  drugs  by  the  mouth,  or  their  excretion,  when  perceptible 
to  the  taste,  by  the  saliva]  is  trismus,  a  tetanic  spasm  of 
the  muscles  of  mastication  which  is  generally  an  introduc- 
tory symptom  of  general  convulsions  (see  Nervous  Sys- 
tem), and  which,  wdth  the  exception  of  the  prevention  of 
the  prehension  of  food,  leads  to  no  special  consequences 
worthy  of  separate  study. 

2.  Deglutition. — Deglutition  can  be  hindered  by  the 
action  of  poisons,  either  through  action  on  the  motor  appa- 
ratus, when  it  is  merely  a  symptom  of  general  paralysis 
(see  Nervous  System),  or  by  alteration  of  the  secretions 
of  the  mouth  and  pharynx,  as,  for  example,  the  dyspha- 
gia produced  by  belladonna  poisoning.  Whether  spasm 
of  the  muscles  of  deglutition,  as  occurs  in  hydrophobia, 
may  be  produced  by  the  action  of  poisons,  is  unknown. 

3.  Movements  of  the  Stomach. — As  the  knowledge 
which  we  possess  as  to  the  conditions  modifying  the 
physiological  movements  of  the  stomach  is  of  the  most 
limited  character,  it  follows  that  nothing  can  be  said  as 
to  the  effects  of  drugs  on  this  function  of  the  digestive 
organs.  As  regards  the  production  of  vomiting  by  toxic 
action,  our  knowledge  is  a  little  more  complete. 

Vomiting  is  a  complicated  co-ordination  of  various  mus- 
cles, having  as  a  result  the  emptying  of  the  contents  of 
the  stomach  into  the  pharynx.  With  the  exception  of  the 
opening  of  the  cardiac  orifice,^  the  role  of  the  stomach  in 
vomiting  is  purely  passive,  the  act  being  largely  due  to 
rhythmic  contractions  of  the  diaphragm  and  abdominal 
muscles.  The  co-ordination  of  these  muscles  is  governed 
by  a  nerve  centre  lying  in    the   medulla  oblongata  or 

»  SchiflF,  Moleschott's  Unters.,  x.  363. 
12* 


138  GENERAL    ACTION    OF    POISONS. 

brain^  which  is  capable  of  being  set  into  activity  by 
stimuli  directly  brought  to  it  by  the  blood,  or  reflexly 
through  various  centripetal  nerves,  especially  those  com- 
ing from  the  digestive  apparatus.  The  determination  as 
to  which  of  these  modes  is  concerned  in  the  production 
of  vomiting  by  drugs  cannot  be  reached  by  merely  vary- 
ing the  mode  and  location  of  administration  of  the  drug, 
since  the  production  of  emesis  after  venous  or  hypoder- 
mic injections  does  not  prove  a  direct  action  on  the 
centre  ;  for  the  substances  are  carried  by  absorption  to 
the  stomach,  and  may  there  serve  as  reflex  stimuli. 
This  statement  is  proved  by  the  fact  that  tartar  emetic 
requires  larger  doses  and  a  longer  time  to  produce 
emesis  when  injected  into  a  vein  than  when  given  by 
the  stomach,  and  even  in  the  former  case  the  presence 
of  antimony  can  always  be  detected  in  the  vomited 
matters.^  It  is,  therefore,  still  doubtful  whether  the 
centre  is  capable  of  direct  stimulation. 

Different  animals  vomit  with  different  degrees  of  readi- 
ness ;  while  birds,  dogs,  and  mice,  vomit  with  the  greatest 
ease,  the  contrary  is  the  case  with  rabbits  and  frogs. 

Although,  as  has  been  said  above,  the  stomach  is  pas- 
sive in  the  act  of  vomiting,  it  is  conceivable  that  drugs 
may  at  the  same  time  produce  active  contractions  of  the 
stomach  ;  to  verify  this,  the  voluntary  muscles  should  be 
paralyzed  with  moderate  doses  of  curare  and  artificial 
respiration  kept  up,  when  the  conditions  of  the  stomach 
may  be  directly  inspected. 

The  consequence  of  the  act  of  vomiting  is  the  removal 
of  the  contents  of  the  stomach,  and,  therefore,  the  partial 
or  total  removal  of  the  poison  ;  if  it  is  desired  to  study 
the  general  action  of  a  poison  which  produces  vomiting, 
the  drug  should  first  be  administered  by  some  other 
means,  as  hypodermically,  and  if  vomiting  still  occurs,  it 
must  be  prevented  by  curare,^  or  by  ligature  of  the  oeso- 

'   Hermann  u.  (jrimm,  Arch.  f.  d.  Ges.  Physiol.,  iv.  205. 

2  Hermann,  Arch.  f.  d.  Ges.  Phys.,  v.  280. 

?  Giannuzzi,  Centbl.  f.  d.  med.  Wissen.,  1865,  i. 


ACTION    ON    THE    DIGESTIVE    APPARATUS.       139 

phagus,  a  procedure  often  employed  in  the  older  experi- 
ments.^ [In  many  cases  vomiting  may  be  prevented  by 
section  of  the  vagi,  since  these  are  the  nerves  by  which 
the  afferent  impulses  which  cause  the  relaxation  of  the 
cardiac  sphincter  reach  the  medulla.] 

4.  Movements  of  the  Intestines. — Alterations  in 
the  movements  of  the  intestines,  such  as  increase,  dimi- 
nution, or  suppression  of  the  peristaltic  motions,  cannot 
be  clearly  studied  either  by  inspection  or  palpation 
without  opening  the  abdomen,  and  it  is  therefore  gener- 
ally advisable  to  expose  the  abdominal  contents  by  an 
incision  in  the  linea  alba  ;  but  since  the  rapid  loss  of  heat 
and  drying  of  the  intestines  lead  to  changes  in  their  cir- 
culation, and  consequently  to  changes  from  the  normal 
motions  which  might  erroneously  be  attributed  to  the 
action  of  the  drugs,  it  has  been  recommended  with  some 
show  of  success  to  immerse  the  animal,  before  opening 
the  abdomen,  in  a  bath  of  salt  solution,  J  per  cent.,  heated 
to  the  body  temperature,  Avhereby  all  cooling  and  access 
of  air  is  prevented ;  under  such  circumstances  artificial 
respiration  must  be  kept  up  through  a  tracheal  canula 
and  rubber  tube.^ 

[Salvioli^  employed  the  following  method  for  studying 
the  movement  of  the  small  intestine.  A  piece  of  jejunum 
is  excised  with  its  mesentery,  from  a  rabbit,  laid  on  the 
inner  surface  of  a  piece  of  excised  abdominal  wall  in  a 
warm,  moist  chamber,  and  a  mixture  of  30  parts  calves- 
blood  and  70  parts  j  per  cent,  salt  solution,  well  shaken 
up  in  the  air,  conducted  through  its  bloodvessels  ;  one  or 
more  light  levers  resting  on  the  surface  of  the  intestine 
serve  to  register  its  movements.  The  action  of  drugs  on 
the  peristaltic  movements  may  be  studied  by  adding  the 
poison  to  the  circulating  fluid ;  thus  Salvioli  found  that 
nicotine  caused  violent  intestinal  contractions  and  narrow- 
ing of  the  bloodvessels,  while  opium  and  atropine  pro- 

1  See  Orfila's  Toxicologie,  1839,  1.  29. 

2  Sanders-Ezii  u.  van  Braam  Houckgeest,  Pflliger's  Arch.  vi.  266. 

3  Arcli   f,  Anat.  u.  Phys.,  1880,  s.  95. 


140  GENERAL    ACTION    OF    POISONS. 

duced  the  reverse.  For  particulars  as  to  this  method,  as 
well  as  for  the  relations  observed  between  the  blood- 
pressure  and  the  peristalsis,  reference  must  be  made  to 
the  original  memoir.] 

Departure  from  the  normal  degree  of  peristaltic  motion 
may  be  due  either  to  direct  action  on  the  muscles  of  the 
intestine  or  on  its  ganglia,  on  the  extrinsic  motor  or  in- 
hibitory (splanchnic)  centres,  or  indirectly  to  respiratory 
or  circulatory  changes. 

The  experiments  necessary  for  the  proof,  by  exclusion, 
as  to  which  of  these  modes  of  action  is  concerned,  such 
as  irritation  and  section  of  the  appropriate  nerves,  will 
readily  suo;fz;est  themselves. 

[Direct  action  of  a  drug  on  the  intestinal  walls,  or  on 
their  contained  ganglia,  may  be  proved  by  the  absence 
of  the  characteristic  symptoms,  such  as  contractions, 
paralysis,  etc.,  in  a  portion  of  the  intestinal  tube  which 
has  been  protected  from  the  access  of  the  poison  by  pre- 
vious ligation  of  the  branch  of  the  mesenteric  artery  by 
which  it  is  supplied.  And,  conversely,  injection  of  the 
poison  into  a  branch  of  the  mesenteric  artery  should, 
under  such  circumstances,  cause  the  symptoms  first  to 
appear  in  the  portion  of  intestine  supplied  by  that  ves- 
sel.] 

It  should,  however,  be  mentioned  that  anaemia  of  the 
abdominal  vessels,  as  well  as  dyspnoea,  causes  an 
increased  peristalsis. 

As  regards  modification  of  the  function  of  defecation, 
either  diarrhoea,  or  constipation  may  be  produced  by 
drugs,  but  as  yet  it  is  not  known  whether  the  changes  are 
due  to  action  on  the  motor  apparatus  of  the  bowels  or  on 
their  secretions.^ 

h.  Alterations  in  the  Sensibility  of,  and  Produc- 
tion OF  Abnormal  Sensations  in  the  Alimentary 
Canal. — Abnormal  sensations,  nausea,  loss  of  appetite, 

1  See  Radziejewski,  Arch.  f.  Anal.  n.  PliysioL,  1870,  i.  [and  Hay, 
Journ.  of  Anat.  and  Physiol.,  1881  and  1882]. 


ACTION    ON    THE    DIGESTIVE    APPARATUS.       141 

and  increased  thirst,  are  very  common  effects  of  poisons, 
especially  when  ojiven  by  the  mouth,  and  so  brought  into 
direct  contact  with  the  sense  organs  ;  the  same  effects 
may,  however,  be  often  produced  when  the  drugs  are 
otherwise  administered.  Reliable  observation  of  such 
effects  can  only  be  obtained  in  experiments  on  man ; 
this  also  applies  to  the  numerous  phases  of  painful  sen- 
sations which  often  follow  the  administration  of  poisons, 
such  as  cardialgia,  colic,  etc.,  the  causation  of  which 
is  always  obscure. 

c.  Alterations  in  the  Digestive  Secretions. — 
Accurate  study  of  such  changes,  further  than  the  mere 
evidence  of  increase  of  saliva  from  its  flowing  from  the 
mouth,  or  decrease  by  dryness  of  the  parts,  can  only  be 
obtained  through  the  production  of  iistulae. 

[The  methods  of  studying  the  action  of  drugs  on  the 
salivary  and  biliary  secretion  will  be  given  under  the 
heading  of  the  action  of  drugs  on  glandular  action. 
Occasionally  some  idea  as  to  the  action  on  the  other 
digestive  secretions  is  to  be  obtained  by  the  analysis  of 
gastric  and  pancreatic  juice  obtained  through  fistulge, 
and  the  examination  of  the  digestive  products  obtained 
in  the  same  manner.  Our  ignorance,  however,  of  the 
conditions,  such  as  nerve-influence,  under  which  these 
secretions  are  formed,  does  not  permit  of  any  very  accu- 
rate studies  in  this  connection ;  and  very  often  quite  as 
correct  notions  may  be  obtained  by  adding  the  drug  to 
artificial  digestive  fluids. 

Dogs  are  most  suitable  for  gastric  fistuloe.  The  ani- 
mal is  first  narcotized  with  opium  or  chloroform,  bound 
on  his  back,  and  the  hair  shaved  from  the  epigastric 
region.  An  incision  is  then  made  through  the  skin, 
commencing  at  the  lower  border  of  the  costal  cartilages, 
and  about  an  inch  and  a  half  to  the  left  of  the  linea  alba, 
and  extending  downward  parallel  to  this  line,  for  a  dis- 
tance a  little  less  than  the  diameter  of  the  flange  of  the 
canula  which  it  is  desired  to  use.  Each  muscular  layer 
is  then  to  be  divided  in  a  direction  parallel  to  its  muscu- 


142  GENERAL    ACTION    OP    POISONS. 

lar  fibres,  and  every  bleeding  point  tied  before  opening 
the  peritoneum.  When  it  is  certain  that  the  bleeding 
has  stopped,  the  peritoneum  is  to  be  opened  on  a  director. 
On  stretching  open  the  wound,  the  stomach  (which  should 
have  been  distended  before  the  operation  by  a  full  meal, 
or  by  inflation  with  air  by  means  of  a  tube  passed  down 
the  oesophagus)  comes  into  view,  its  oblique  muscular 
structure  being  plainly  visible  through  its  serous  cover- 
ing. A  point  of  the  gastric  wall  should  now  be  seized 
with  artery  forceps  at  a  spot  where  there  are  not  many 
large  vessels,  and  drawn  forward.  Two  strong  silk 
threads  are  then  passed  into  the  walls  of  the  stomach 
with  a  curved  needle,  at  a  distance  from  each  other  about 
equal  to  the  diameter  of  the  tube  of  the  canula,  and 
brought  out  at  a  similar  distance  from  the  points  where 
they  were  introduced.  An  incision  rather  shorter  than 
the  diameter  of  the  tube  of  the  canula,  is  then  made  into 
the  gastric  walls  between  the  two  threads,  and  the 
opening  stretched  with  blunt  hooks  until  it  is  large 
enough  to  admit  the  inner  flange  of  the  canula.  The 
stomach  is  then  tied  to  the  canula  by  the  threads  pre- 
viously passed  into  its  walls,  and  their  ends  then  passed 
through  the  abdominal  walls  and  tied,  thus  serving  not 
only  to  close  the  wound  in  the  latter,  but  also  to  main- 
tain them  in  apposition  with  the  stomach.  The  canula 
should  be  left  uncorked  for  an  hour  or  so  after  the  ope- 
ration so  as  to  prevent  the  passing  of  the  gastric  contents 
into  the  peritoneal  cavity,  should  the  animal  vomit.  The 
dog  must  be  fed  on  milk  for  two  or  three  days  after  the 
operation,  and  kept  in  a  warm  place. 

The  form  of  canula  almost  universally  used,  is  that 
designed  by  Bernard.  It  consists  of  two  silver  or 
nickel-plated  tubes,  each  of  which  has  at  one  end  a  broad 
flange  ;  one  tube  screws  into  the  other,  so  that  the  dis- 
tance between  the  two  flanges  may  be  altered  at  will. 
On  the  second  or  third  day  after  the  operation,  the  mar- 
gin of  the  wound  becomes  very  much  swollen ;  this 
arrangement  of  the  tubes  permits  the  lengthening  of  the 
canula,  so  that  the  skin  is  not  ulcerated  from  pressure 


ACTION    ON    THE    DIGESTIVE    APPARATUS.       143 

of  the  flange.  The  canula  may  be  closed  by  a  cork 
soaked  in  a  decoction  of  colocynth,  to  prevent  the  dog 
from  tearing  it  out  with  his  teeth. 

Ordinarily  the  animal  will  be  ready  for  experiment  in 
about  a  week.  Comparative  experiments  may  then  be 
made  on  the  characters  of  the  digestive  process  at  stated 
intervals  before  and  after  the  administration  of  the  drugs, 
of  the  changes  in  the  secretion  or  the  drug,  and  of  the 
absorbability  of  the  poison.  Gastric  juice  can  also  be 
collected  for  experiments  on  artificial  digestion:  or  infu- 
sions or  glycerine  extracts  of  the  mucous  membrane  of 
the  stomach  in  0.2  per  cent.  HCl.  may  be  employed. 

The  action  of  drugs  on  the  pancreatic  secretion  is 
as  yet  an  entirely  unbroken  field.  The  extreme  suscep- 
tibility of  the  pancreas  to  disturbing  influences  will  ren- 
der the  study  of  the  action  of  drugs  on  its  secretion,  as 
obtained  in  temporary  fistulae,  liable  to  complication, 
while  it  is  probable  that  it  is  impossible  to  retain  a  nor- 
mal condition  of  the  gland  in  permanent  fistulge. 

If  it  is  desired  to  attempt  studies  on  these  points,  pro- 
bably the  best  method  would  be  to  open  the  abdomen  of 
a  dog  under  warm  salt  solution,  insert  a  canula  in  the 
pancreatic  duct,  and  inject  the  drug  into  the  gland  artery. 
The  method  for  establishing  temporary  or  permanent 
pancreatic  fistulae,  may  be  found  in  Sanderson's  or 
Cyon's  Hand-book,  or  in  Bernard's  waitings.] 

Diminution  of  the  secretions  may  cause  dysphagia  or 
constipation,  or  changes  in  the  digestive  processes ;  in- 
creased secretion  may  produce  diarrhoea. 

The  question  as  to  whether  the  retained  products  of 
secretion  in  the  blood  produce  further  disturbance  of 
function  when  the  secretory  processes  are  interrupted, 
can  only  be  raised  in  the  case  of  the  bile,  and  even  here 
it  is  clouded  with  a  great  deal  of  obscurity.  At  any  rate, 
the  retained  substances  cannot  be  regarded  as  bile,  which, 
as  such,  is  only  elaborated  in  the  liver.  The  possibility 
of  retention  of  bile  through  toxic  action  on  the  intestinal 
canal  (catarrh  leading  to  obstruction  of  the  bile-duct), 
should  be  borne  in  mind.     Such  a  state  of  afi'airs  is  dis- 


144  GENERAL    ACTION    OF    POISONS. 

closed  by  the  paleness  and  abnormal  odor  of  the  feces, 
through  the  jaundiced  color  of  the  skin  and  certain  mucous 
membranes,  and  by  the  presence  of  the  bile  acids  and 
coloring  matters  in  the  urine.  The  existence  of  icterus 
gravis  would  indicate  that  the  retained  bile  products 
may,  under  certain  illy-defined  conditions,  be  the  cause 
of  further  disturbances  of  function. 

d.  Alteration  in  the  Digestive  Processes. — The 
presence  of  poisons  in  the  alimentary  canal  can  lead  in 
the  most  various  ways  to  digestive  disorders ;  either 
through  alteration  in  the  reaction  of  the  digestive  juices, 
through  action  on  the  food  stuffs  or  their  digestive 
products,  through  preventing  the  formation  of  normal 
secretions,  or  by  action  on  their  ferments,  or  finally  by 
interfering  with  the  normal  fermentative  processes.  Any 
one  or  all  of  these  conditions  may  be  produced,  either 
by  directly  swallowing  the  poison  or  through  its  passing 
from  the  blood  into  the  secretions.  The  consequences 
of  disordered  digestion  are  first  seen  in  sensory  distur- 
bances, as  loss  of  appetite,  nausea,  or  colic  ;  then  in 
motor  disturbances,  as  vomiting,  diarrhoea,  or  constipa- 
tion, and,  when  long  continued,  in  emaciation  and  weak- 
ness. 

The  proof  of  such  toxic  changes  is  best  obtained 
through  artificial  digestion  experiments  in  which  the  poi- 
son is  mixed  with  the  digestive  fluids,  though  occasion- 
ally some  idea  as  to  the  action  may  be  obtained  from 
examination  of  the  vomited  matters  or  feces,  or  by  care- 
ful analysis  of  the  symptoms  produced. 


Section  IV.^ — Action  on  Glandular  Organs. 

a.  Secreting  Glands. — The  character  of  the  influ- 
ence of  poisons  on  glandular  organs  is  best  made  out 
through  study  of  their  secretions  ;  nearly  always  the 
changes  which  will  be  detected  will  be  of  a  quantitative 
nature,  and  are  generally  easily  enough  determined,  while 


ACTION  ON  GLANDULAR  ORGANS.      145 

qualitative  changes  produced  by  toxic  action  have  been 
but  rarely  studied. 

The  mode  in  which  drugs  increase  or  diminish  secre- 
tions is  as  obscure  as  the  general  physiological  processes 
connected  with  the  normal  act.  In  many  cases,  doubt- 
less, the  act  is  of  a  vaso-motor  nature,  as  in  the  increased 
salivation  produced  by  curare  ;  in  other  cases  direct 
action  on  the  secretory  tissues  or  nerves  must  be  con- 
cerned.^ A  thorough  investigation  is  possible  in  the  case 
of  but  few  glands  ;  in  the  case  of  the  salivary  glands, 
however,  this  branch  of  pharmacology  has  been  compara- 
tively thoroughly  worked  out. 

1.  [Action  on  the  Salivary  Secretions. — In  order 
to  study  the  action  of  drugs  on  the  salivary  secretion  it  is 
necessary  to  establish  temporary  salivary  fistulse  in  the 
lower  animals,  and  expose  the  nerves  through  whose 
action  modifications  of  the  act  of  secretion  can  be  pro- 
duced. Large  dogs  are  the  most  suitable  for  such  opera- 
tions. 

Since  the  submaxillary  gland  is  the  most  accessible  it 
is  the  gland  which  is  ordinarily  selected  for  such  studies. 

To  make  a  temporary  salivary  fistula  in  a  dog,  the 
animal  is  chloroformed,  the  hair  shaved  from  the  lower 
surface  of  the  jaw  and  the  side  of  the  neck,  and  an  inci- 
sion made  along  the  inner  border  of  the  lower  jaw,  com- 
mencing about  its  anterior  third  and  extending  back  to  the 
transverse  process  of  the  atlas,  dividing  the  skin  and 
platysma  muscle.  After  clearing  away  the  connective 
tissue  and  fat,  carefully  avoiding  all  veins,  the  submaxil- 
lary gland  comes  into  view,  just  below  the  angle  of  the 
jaw.  It  is  then  seen  that  the  gland  lies  in  an  angle 
formed  by  the  junction  of  two  veins  which  go  to  make 
up  the  external  jugular,  one  branch  coming  from  above 
downward,  directly  behind  the  gland,  and  usually  receiv- 
ing a  small  vein  from  the  gland  itself  (as  represented  in 
Fig.  31),  while  the  lower  branch  runs  horizontally  below 

'  Heidenhain,  Pfluger's  Archiv,  v.  309. 
13 


116 


GENERAL    ACTION    OF    POISONS. 


the  gland,  and  is  formed  by  the  junction  of  two  other 
branches,  one  coming  from  above  and  the  other  from  be- 
low ;  this  horizontal  branch  very  constantly  receives  a 
vein  from  the  gland.  This  dissection  requires  care,  to 
avoid  wounding  these  large  veins. 

Fig.  31. 


Veins  of  the  submaxillary  gland  of  the  dog. 
maxillary  gland.     B.  Jugular  vein. 


(After  Bernard.) 
C.   Glandular  veil 


A.  Sub. 


Both  branches  which  go  to  form  the  horizontal  branch 
are  now  to  be  tied,  the  one  coming  from  above  receiving 
a  double  liorature,  one  where  it  comes  over  the  ramus  of 
the  jaw  and  the  other  Avhere  it  joins  its  fellow,  the  inter- 
mediate portion  being  removed.  Having  now  carefully 
removed  the  cellular  tissue  from  the  portion  of  the  wound 
in  front  of  the  gland,  the  thick  belly  of  the  digastric 
muscle  comes  into  view,  its  fibres  running  forward  from 
its  origin  on  the  temporal  bone,  to  be  inserted  in  the 
middle  third  of  the  ramus  of  the  lower  jaw,  immediately 
in  front  of  the  insertion  of  the  masseter,  from  which 
muscle  it  is  separated  by  a  slight  groove.  In  front  of 
the  digastric  the  floor  of  the  wound  is  formed  by  the 
transverse  fibres  of  the  mylo-hyoid  muscle,  crossed  by 
the  mylo-hyoid  nerve,  which  comes  out  from  under  the 
jaw  at  the  point  of  insertion  of  the  digastric  muscle. 


ACTION    ON    GLANDUL'VR    ORGANS. 


147 


The  connective  tissue  is  then  gradually  to  be  cleared 
away,  with  a  blunt  hook,  from  the  surface  of  the  digas- 


fcJD 


trie  muscle,  and  from  the  groove  between  it  and  the 
masseter  muscle,  taking  care  to  avoid,  as  the  deeper 
portion  is  reached,  the  facial  artery,  which  passes  over 


148  GENERAL    ACTION    OF    POISONS. 

the  jaw  to  run  between  these  muscles,  and  the  artery  to 
the  gland  which  comes  from  the  facial  and  goes  in  this 
groove  back  to  the  gland.  In  the  same  locality  lie  also 
the  ducts  of  the  gland  and  the  chorda  tympani  nerve. 
The  digastric  muscle  is  now  to  be  separated,  with  an 
aneurism  needle,  from  the  facial  artery,  avoiding  all  the 
adjacent  structures,  and  its  muscular  arterial  branch 
tied.  The  muscle  is  then  divided  at  its  anterior  third, 
or  where  it  is  inserted  into  the  jaw,  and  its  posterior  ex- 
tremity seized  with  a  pair  of  artery  forceps,  and  gradu- 
ally cleared  back  to  its  insertion  into  the  temporal  bone, 
and  surrounded  by  a  ligature.  Now,  when  it  is  assured 
that  there  is  nothing  but  muscular  structure  in  the  grasp 
of  the  ligature,  it  is  pushed  back  to  the  temporal  bone 
and  tightened,  and  the  digastric  muscle  divided  in  front 
of  the  ligature  and  removed.  On  carefully  tearing  away 
the  connective  tissue  at  the  base  of  the  wound,  and  draw- 
ing back  the  submaxillary  gland,  there  is  exposed  a  tri- 
angular cavity  (represented  in  Fig.  32). 

This  space  is  limited  above  and  behind  by  the  deep 
surface  of  the  submaxillary  gland,  into  the  hilum  of 
which  enter  the  artery,  chorda  tympani,  and  sympathetic 
nerve  fibres  with  the  glandular  duct.  Its  lower  margin 
is  formed  by  the  genio-hyoid  muscle,  and  the  upper 
border  by  the  ramus  of  the  jaw  and  the  masseter  muscle  ; 
the  anterior  portion  of  its  floor  is  formed  by  the  trans- 
verse fibres  of  the  mylo  hyoid  muscle,  on  which  ramify 
the  branches  of  the  mylo-hyoid  nerve. 

At  the  posterior  portion  of  this  space  the  external 
carotid  artery  enters  and  runs  along  the  base  of  the  tri- 
angle, giving  off  first  the  lingual  and  then  the  facial  arte- 
ries, from  the  latter  of  which  comes  the  artery  of  the 
gland. 

Almost  immediately  after  entering  this  space  the  caro- 
tid is  crossed  by  the  large  h3^poglossal  nerve,  running 
forward  to  be  distributed  to  the  muscles  of  the  tongue, 
etc.  Now,  if  this  nerve  is  divided  at  the  point  where  it 
crosses  the  carotid,  and  the   central   end   removed,  the 


ACTION  ON  GLANDULAR  ORGANS.      149 

pneumogastric  trunk  comes  into  view,  lying  behind  the 
artery.  On  pulling  to  one  side  the  vagus  trunk,  below 
and  behind  it  can  be  seen  the  white  trunk  of  the  sympa- 
thetic nerve,  which  here  separates  itself  from  the  vagus 
to  form  the  superior  cervical  ganglion,  from*  which  two 
small  filaments  pass  out  to  accompany  the  carotid  and 
glandular  artery  to  enter  the  hilum.  Some  of  the  sym- 
pathetic fibres  also  pass  into  the  gland  along  the  arterial 
branch  which  comes  from  the  temporal  artery  and  enters 
the  superior  part  of  the  gland. 

Then,  to  expose  the  chorda  tympani  and  the  salivary 
ducts,  the  fibres  of  the  mylo-hyoid  muscle  are  to  be 
divided  transversely  at  about  their  middle,  avoiding  the 
nerve  and  tying  all  veins,  and  the  upper  half  of  the  mus- 
cle reflected.  The  lingual  nerve  then  comes  into  view, 
passing  from  under  the  ramus  of  the  jaw,  and  running 
downward  and  forward  about  parallel  in  direction  with 
the  hypoglossal.  On  drawing  the  parts  toward  the  mid- 
dle line,  the  two  salivary  ducts  are  seen  passing  along 
close  together,  immediately  under  the  ramus  of  the  jaw, 
the  submaxillary  duct  lying  nearest  the  bone  and  being 
a  little  the  largest. 

On  tracing  back  the  lingual  nerve  to  where  it  passes 
from  under  the  jaw,  it  Avill  be  seen  that  a  delicate  ner- 
vous filament  here  leaves  the  lingual  and  curves  back- 
ward, along  with  the  ducts,  to  enter  the  hilum  of 
the  gland ;  this  is  the  chorda  tympani.  Immediately 
after  the  chorda  leaves  the  lingual  there  is  sometimes 
seen  a  small  ganglionic  enlargement,  known  as  the  sub- 
maxillary ganglion,  and  as  the  chorda  enters  the  hilum 
it  forms  a  slight  ganglionic  plexus  with  the  fibres  of  the 
sympathetic. 

Each  of  the  nerves,  which  it  is  desired  to  study, 
should  be  carefully  isolated  and  surrounded  with  a 
thread,  and  a  canula  should  be  inserted  into  the  submax- 
illary duct.  To  f^icilitate  this  last  step  the  duct  should 
be  freed  slightly  from  the  connective  tissue  and  closed 
with  a  clip  or  a  ligature,  as  near  the  mouth  as  possible. 
Then  the  chorda  should  be  stimulated,  so  as   to  distend 

13* 


150  GENERAL    ACTION    OF    POISONS. 

the  duct  with  saliva,  and  a  small  slip  of  wood  or  card 
passed  under  it,  to  act  as  a  support.  Now,  if  one  edge 
of  the  duct,  over  the  support,  is  seized  by  an  assistant 
with  a  pair  of  line  forceps,  while  the  operator  seizes  the 
opposite  edge,  and  the  duct  is  snipped  between  the  two 
with  a  pair  of  sharp-pointed  scissors,  the  canula  can  be 
readily  inserted. 

The  secretion  of  submaxillary  saliva  is  a  reflex  act,  for 
which  the  lingual  and  glosso-pharyngeal  nerves  (to- 
gether with  certain  other  nerves),  serve  as  the  aiferent 
fibres,  the  centre  lies  in  the  medulla,  while  the  eff"erent 
secretory  fibres,  together  with  vaso  dilator  fibres,  pass 
through  the  chorda  tympani  nerve.  Drugs  may,  there- 
fore, cause  an  increased  salivary  secretion  through 
stimulation  of  any  of  these  three  divisions  of  the  reflex 
circle,  while  the  majority  of  instances  in  which  the 
secretion  is  diminished  will  be  found  to  depend  upon 
paralysis  of  the  chorda  tympani. 

Thus,  when  it  is  found  that  the  injection  of  a  drug 
into  the  venous  system  causes  a  diminution  of  the  salivary 
secretion,  determined  by  allowing  the  saliva  to  flow  from 
the  submaxillary  duct  into  a  graduated  vessel,  it  will  be 
ordinarily  found  (as  in  the  case  of  atropia)  that  the 
stimulation  of  the  chorda  fails  to  produce  a  flow  of 
saliva  ;  should,  however,  it  be  followed  by  the  ordinary 
result,  increased  flow  and  increased  vascularity  of  the 
gland,  it  may  then  be  assumed  that  the  paralysis  lies  in 
the  centre  or  afferent  nerves.  When  the  paralysis  has 
been  located  in  the  chorda  tympani,  the  results  of  the 
antagonistic  action  of  some  known  stimulus  of  this  nerve, 
such  as  pilocarpine,  should  then  be  tested  by  injecting  a 
few  milligrammes  into  the  carotid  artery  of  the  same  side, 
or  directly  into  the  duct  of  the  gland. 

In  most  instances  it  will  be  found  that  the  paralysis  of 
the  chorda  can  be  removed  by  pilocarpine,  and  toxic 
stimulation  of  the  chorda,  by  atropine.] 

2.  [Action  on  the  Biliary  Secretion. — The  action 
of  drugs  which  modify  the  amount  of  bile  discharged  from 
the  liver  may  fall  under  two  categories  :  either  action  on 


ACTION    ON    GLANDULAR    ORGANS.  151 

the  bile-secreting  or  the  bile  expelling  mechanisms.  It 
is  probable  that  these  two  processes  are  closely  united, 
though  many  instances  might  be  given  of  drugs,  such  as 
gamboge  or  magnesium  sulphate,  which,  although  power- 
ful intestinal  stimuli  (and  we  know  that  it  is  from  the 
stimulation  of  the  intestinal  mucous  membrane  with  the 
acid  chyme  that  the  bile  is  normally  discharged),  and 
therefore  probably  possessing  the  power  of  causing  a  re- 
flex contraction  of  the  gall-bladder  and  expulsion  of  bile, 
cannot  be  regarded  as  stimulants  to  the  secretion  of  bile. 
The  determination  of  the  point  as  to  whether  a  drug  is 
a  stimulant  of  the  expelling  mechanism  is,  however,  very 
much  less  important  than  as  to  whether  the  substance  is 
a  true  hepatic  stimulant  or  not;  we  will  accordingly  at 
present  simply  give  the  methods  of  examining  the  action 
of  drugs  on  the  secretory  functions  of  the  liver.  At 
the  outset,  we  might  say  that  drugs  which  stimulate  in- 
testional  secretion  usually  depress  hepatic  secretion,  and 
while  drugs  which  produce  slight  catharsis  only  slightly 
modify  the  amount  of  bile  secreted,  powerful  purgation 
produces  a  marked  depression.  The  method  of  study- 
ing the  action  of  drugs  on  the  hepatic  secretion,  as  em- 
ployed by  Rutherford,^  is  by  means  of  temporary  biliary 
fistulse  in  curarized  drugs.  He  has  found  that  when 
artificial  respiration  is  maintained  in  curarized  dogs,  the 
secretion  of  bile  remains  tolerably  uniform  duHng  the 
first  four  or  five  hours  after  the  commencement  of  the 
experiment,  but  falls  slightly  as  a  longer  period  elapses. 
The  composition  of  the  bile  remains  constant. 

The  dog  should  receive  a  full  meal  of  lean  meat  the 
day  before  the  experiment,  so  as  to  allow  of  complete 
digestion  and  absorption  before  the  investigation  is  un- 
dertaken. The  animal  is  then  fastened  on  his  back,  cur- 
arized and  artificial  respiration  maintained,  and  a  glass 
canula  inserted  through  an  opening  in  the  linea  alba  into 
the  common  bile-duct,  near  its  entrance  into  the  duo- 
denum, and  tied  therein.    A  rubber  tube  is  then  attached 

'  Trans.  Roy.  Soc.  of  Ediiiburgli,  vol.  xxix.  1879. 


162  GENERAL    ACTION    OF    POISONS. 

to  the  canula,  the  gall-bladder  pressed  so  as  to  expel  its 
contents  and  fill  the  tube,  and  the  cystic  duct  then 
clamped :  the  flow  of  bile  can  be  estimated  by  allowing 
it  to  drop  from  the  rubber  tube  into  a  graduated  vessel. 

The  wound  in  the  abdomen  must  be  closed,  and  the 
animal  covered  with  cotton-wool  to  prevent  loss  of  tem- 
perature. After  estimating  the  rapidity  of  flow  for  half 
an  hour  or  longer,  the  drug  can  then  be*^ injected  into  the 
duodenum,  by  a  syringe  with  a  needle  point.  It  should 
be  mentioned  that  the  bile  always  flows  much  more 
rapidly  in  the  first  few  minutes  of  an  experiment.] 

Wherever  the  direct  contact  of  the  poison  with  a 
mucous  membrane  is  found  to  produce  a  catarrhal  increase 
of  secretion,  or  when,  under  similar  circumstances,  ana- 
tomical alterations  can  be  made  out  in  the  glands  of  the 
mucous  membranes,  the  results  may  always  be  attributed 
to  direct  actions  on  the  tissues. 

3.  Action  on  the  Renal  Secretion. — Functional  dis- 
turbances of  the  kidneys  are  during  life  only  capable  of 
being  studied  through  the  character  of  the  secretion,  which 
may,  through  the  action  of  poisons,  be  increased,  dimin- 
ished, or  altered  in  character.  These  alterations  may  con- 
sist either  in  the  admixture  of  the  poison  itself  or  in  the  pres- 
ence, induced  by  the  poisoning,  of  abnormal  ingredients, 
such  as  blood-corpuscles,  haemoglobin,  albumen,  bile  mat- 
ters, sugar,  lactic  acid,  leucin,  tyrosin,or  finally  in  mere 
alterations  in  the  quantitative  composition  of  the  urine  re- 
sulting from  modified  tissue  changes  induced  by  the  poison. 
The  kidneys  themselves  are  not  always  actively  concerned 
in  the  production  of  these  alterations  in  the  urine.  It  may, 
however,  be  assumed  that  the  kidneys  are  concerned  in  di- 
minution or  abnormal  quantity  of  urine,  which,  however, 
can  also  be  a  result  of  toxic  alterations  in  blood-pressure, 
when  blood-corpuscles  or  haemoglobin  appear  in  the  urine  ; 
in  such  cases  there  exists  a  toxic  inflammation  of  the  kid- 
ney parenchyma  which  is  capable  of  post-mortem  demon- 
stration. On  the  other  hand,  it  appears  that  toxic  alter- 
ations of  kidney  structure,  such  as  are  often  met  with  in 


ACTION    ON    GLANDULAR    ORGANS.  153 

fatty  degeneration,  may  exist  without  rendering  their 
presence  at  all  evident  by  any  alterations  in  the  urine. 
Such  appearances  often  produce  definite  effects  on  the 
entire  organism.  The  excretion  of  the  poison  in  the 
urine  can,  as  already  remarked,  lead  to  the  entire  re- 
moval of  the  poison  from  the  body,  and  can  even  render 
a  poison  absolutely  innocuous.  On  the  other  hand,  it  is 
conceivable  that  the  occurrence,  during  the  poisoning,  of 
a  disordered  functional  activity  of  the  kidney,  may  sud- 
denly increase  the  proportion  of  poison  in  the  blood,  and 
thus  lead  to  intensified,  or  new  symptoms  of  poisoning  ;  it 
is  consequently  a  priori  probable  that  a  similar  train  of 
symptoms  would  follow  the  administration  of  the  drug  to 
a  system  in  which  the  kidneys  were  already  similarly 
affected.  The  presence  of  the  poison  in  the  urine  may 
lead  to  inflammation  of  the  bladder  and  ureters  in  the 
same  way  that  the  inflammation  of  the  kidneys  may  be 
produced  by  the  passage  of  the  poison  through  the  kid- 
neys into  the  urine. 

Anuria  and  polyuria,  when  of  extended  duration,  may 
produce  pathological  effects  upon  the  system  ;  urgemia  and 
retention  of  water  in  the  first  case,  severe  thirst  in  the 
other.  The  presence  of  abnormal  constituents  in  the 
urine  is  only  of  any  general  moment  when  they  consist 
of  unoxidized  substances,  such  as  sugar  and  albumen, 
and  therefore  entail  a  loss  of  nutritious  principles. 

[The  secretion  of  urine  may  be  increased  by  all  causes 
which  produce  an  increased  blood-pressure  in  the  renal 
glomeruli :  hence  drugs  may  act  as  diuretics  which  in- 
crease the  force  or  frequency  of  the  heart's  beat,  which 
cause  contractions  of  bloodvessels  supplying  other  organs 
(as  the  skin),  or  which  cause  relaxation  of  the  renal 
arteries.  Thus,  profuse  renal  secretion  may  be  caused  by 
section  or  paralysis  of  the  renal  nerves,  from  the  increased 
pressure  in  the  glomeruli  consequent  on  tlie  relaxation  of 
the  renal  arteries ;  while,  conversely,  diminished  secre- 
tion may  follow  stimulation  of  the  renal  or  splanchnic 
nerves.  All  drugs,  therefore,  which  produce  increased 
arterial  tension  will  not  act  as  diuretics  unless  they  at 


154  GENERAL    ACTION    OF    POISONS. 

the  same  time  cause  relaxation  of  the  renal  arteries;  thus, 
when  strychnia  is  injected  into  the  circulation  it  causes 
diminution  of  secretion  from  constriction  of  all  the  arte- 
rioles, so  acting  like  stimulation  of  the  medulla  ;  but 
when  the  splanchnics  or  renal  nerves  are  first  divided, 
injections  of  strychnia  then  produce  increased  urinary- 
flow. 

In  addition,  however,  to  the  modifications  of  renal 
secretion  duetto  alterations  in  blood-pressure,  drugs  may 
act  as  diuretics  by  directly  stimulating  the  renal  epithe- 
lium. 

The  rate  of  urinary  secretion  may  be  estimated  by 
opening  the  abdomen  and  inserting  canulse  into  the  ure- 
ters ;  the  canulse  are  then  attached  to  rubber  tubes  by 
which  the  secretion  is  conducted  externally  into  graduated 
glass  vessels. 

To  introduce  canulae  into  the  ureters,  their  lower  por- 
tion, just  before  their  entrance  into  the  bladder,  should 
be  selected.  The  abdomen  may  be  opened,  after  emp- 
t^^ing  the  bladder  and  rectum,  by  an  incision  on  each 
side  of  the  recti  abdominis  muscles  or  directly  opposite 
the  sacro-iliac  symphysis,  and  should  be  long  enough  to 
admit  two  fingers  :  when  the  last  of  the  above-mentioned 
incisions  is  employed,  the  ureters  can  readily  be  recog- 
nized by  the  touch  at  the  points  where  they  cross  the 
iliac  arteries.  Instead  of  the  ordinary  straight  canuUie, 
it  is  better  to  employ  glass  or  metal  canulae  bent  at  a 
right  angle,  the  long  arm  having  a  length  sufficient  to 
extend  through  the  abdominal  wound  after  the  short  arm 
has  been  inserted  and  bound  fast  into  the  ureter ;  by 
this  means  kinking  of  the  tube  is  prevented. 

To  study  the  changes  in  the  renal  circulation  produced 
by  poisons,  either  the  method  employed  by  Ludwig  and 
Mosso  may  be  used,  or  the  oncograph  devised  by  Dr. 
Boy. 

To  maintain  artificial  circulation  through  the  kidney 
according  to  Ludwig's  method,  the  carotid  artery  of  a 
dog  is  opened  and  as  much  blood  as  possible  collected  and 
defibrinated.     The  abdomen  is  then  opened  and  a  canula 


ACTION    ON    GLANDULAR    ORGANS.  155 

inserted  into  the  renal  artery  and  another  into  the  renal 
vein,  the  vessels  being  first  compressed  with  clips  so  as 
to  prevent  the  entrance  of  air.  The  kidney  is  then  ex- 
cised with  the  greatest  possible  care  and  placed  in  the 
warm  chamber,  the  arterial  canula  being  connected  with 
the  flask  containing  the  defibrinated  blood,  under  definite 
pressure,  and  the  rapidity  of  blood-flow  from  the  renal 
vein  estimated.  The  substance  being  experimented  with 
is  then  added  to  tlie  arterial  blood,  and  comparisons  of 
this  rate  of  flow  made.  This  method  as  employed  by 
Mosso^  also  permits  the  estimation  of  changes  in  volume 
of  the  organ  from  varying  blood-supply  ;  but  since  the 
plan  pursued  by  Dr.  Roy  enables  similar  studies  to  be 
made  on  the  kidney  while  still  in  connection  with  the 
natural  blood-supply,  it  is  to  be  preferred  as  less  liable 
to  error.  Dr.  Roy^  has  found  that  the  degree  of  expan- 
sion of  the  bloodvessels  of  the  kidney  furnishes  an  ex- 
tremely reliable  idex  as  to  the  secretory  processes  going 
on  in  the  organ.  His  method  consists  in  inclosing  the 
kidney,  after  its  exposure  through  an  incision  in  the  lum- 
bar region,  in  a  rigid  metal  box,  of  appropriate  shape, 
containing  oil,  and  of  such  a  construction  that  while  no 
hindrance  is  ofiered  to  the  entrance  or  exit  of  blood  by 
the  renal  arteries  or  veins,  any  change  in  the  volume  of 
the  organ  causes  a  rise  or  fall,  corresponding  in  extent, 
of  a  recording  lever  writing  upon  the  moving  paper  of 
the  kymographion.  The  number  of  drops  of  urine  which 
fall  from  a  canula  tied  into  the  ureter  can  also  be  re- 
corded on  the  same  paper,  by  allowing  each  drop  as  it 
falls  to  close  an  electric  current  flowing  through  the 
bobbins  of  an  electro-magnetic  signal.  In  all  such  ex- 
periments, the  blood-pressure  must  be  also  recorded,  other- 
wise serious  errors  may  be  made  in  drawing  conclusions 
as  to  the  nature  of  various  changes  in  the  volume  of  the 
organ.  For  recording  changes  in  the  volume  of  the  kid- 
ney, two  separate  instruments  are  employed,  the  one  in- 

1  Ludwig's  Arbeiten,  1874. 

2  Journ.  of  Phys.,  Jan.  1828. 


156  GENERAL    ACTION    OF    POISONS. 

closing  the  organ  and  the  other  for  recording  graphically 
the  changes  in  its  volume.  The  form  of  box  which  Dr.  Roy 
employed  in  his  investigations  on  the  spleen^  is  equally 
suitable  for  studies  of  changes  in  volume  of  the  kidney. 
It  consists  of  an  elongated  sheet-metal  box,  composed  of 
two  symmetrical  halves  which  are  joined  together  by 
a  couple  of  hinges.  Each  of  these  halves  is  composed 
of  an  outer  and  inner  shell,  the  latter  of  which  fits 
accurately  into  the  former,  and  the  two  are  capable 
of  being  firmly  screwed  to  one  another  by  means  of 
screws  on  the  upper  and  lower  rounded  edges  of  the 
box.  Between  the  two  shells  is  clamped  the  edge  of  a 
thin  flexible  membrane  prepared  from  the  peritoneum 
of  the  calf.  The  membrane  is  so  arranged  as  to  form  an 
air-tight  chamber  which  is  bounded  on  the  one  side  by 
the  flaccid  membrane,  and  on  the  other  by  the  metal  wall 
of  the  box.  In  each  of  the  two  chambers  thus  produced, 
there  are  two  openings,  one  pair  of  which  is  connected 
with  a  T-tube,  and  thereby  with  the  recording  apparatus  ; 
the  other  two  openings  are  fitted  with  small  taps,  and 
are  simply  intended  to  allow  the  air  to  escape,  when  the 
chambers  are  filled  with  oil  after  the  kidney  has  been 
introduced  into  the  box.  At  the  point  of  junction  of 
the  two  halves  of  the  box  on  the  side  opposite  to  the 
hinges  is  a  narrow  slit  formed  by  an  indent  in  the  edges 
of  the  two  halves,  which  slit  is  intended  to  permit  of  the 
passage  of  the  renal  vessels  and  ureter.  The  recording 
instrument  communicates  with  the  interior  of  the  two 
chambers  of  the  box  ;  its  principle  is  similar  to  that  of 
Dr.  Roy's  instrument  already  described  for  studying  the 
work  done  by  the  heart. 

In  order  to  make  the  experiment,  the  animal  is  anaes- 
thetized, a  canula  inserted  into  the  carotid  artery  for 
blood-pressure  observation,  and  one  into  the  jugular 
vein  for  the  injection  of  the  poison.  The  kidney  is  then 
exposed  by  an  incision  in  the  lumbar  region,  and  gently 
inserted  into  the  box  which  should  have  been  previously 

J  Journ.  of  PhjsioL,  Jan.  1882. 


ACTION    ON    GLANDULAR    ORGANS.  157 

warmed  to  the  body  temperature,  and  the  two  chambers 
of  the  box,  and  the  tube  connecting  the  box  with  the  re- 
cording instrument  filled  with  warm  olive  oil.] 

4.  Action  on  the  Sweat  Glands. — It  is  here  worthy 
of  notice,  that  many  drugs  may  either  produce  an  abnormal 
sweat  secretion,  may  reduce  the  normal  amount,  or  may 
themselves,  or  their  products,  pass  into  the  excretion. 

[  rhe  secretory  activity  of  the  sweat  glands,  like  other 
secretory  processes,  is  largely  dependent  upon  the 
amount  of  blood  supplied  to  the  organ ;  hence  drugs 
which  produce  vaso-motor  paralysis  of  the  skin,  will 
tend  to  produce  an  increased  secretion  of  sweat,  and 
conversely,  a  diminished  blood  supply  to  the  sweat 
glands  will  reduce  their  secretions.  The  comparatively 
recent  experiments,  however,  of  Goltz,  Luchsinger,  Nau- 
roci,  Vulpian,  and  others,  show  that  there  are  special 
nervous  mechanisms  governing  the  secretion  of  sweat  as 
complete  as  had  been  previously  discovered  in  the  case 
of  the  salivary  glands.  When  the  peripheral  end  of  a 
divided  sciatic  nerve  in  a  dog  or  cat  is  stimulated  with  an 
interrupted  current,  a  profuse  sweat  is  poured  out  on  the 
ball  of  the  foot.  While  this  secretion,  as  in  the  case  of 
the  saliva  which  follows  stimulation  of  the  chorda  tym- 
pani,  is  to  a  certain  extent  governed  by  the  vaso-motor 
paralysis  thereby  produced,  it  is  not  entirely  dependent 
upon  it,  as  the  same  results  will  follow  after  clamping 
the  aorta,  or  even  in  an  amputated  limb  ;  while  the 
analogy  with  the  salivary  secretion  is  made  still  more 
complete  by  the  fact  that  atropia  will  paralyze  the  secre- 
tory fibres  of  the  sciatic,  leaving  the  vaso-motor  fibres 
intact.  Then,  again,  it  has  been  found  that  there  exist 
special  centres  in  the  spinal  cord  through  whose  stimu- 
lation a  reflex  secretion  of  sweat  can  be  produced.  Thus, 
if  the  central  end  of  a  divided  sciatic  is  stimulated,  all 
the  limbs,  with  the  exception  of  the  one  in  which  the 
nerve  has  been  divided,  will  perspire  ;  or,  if  after  division 
of  one  sciatic  the  animal  is  exposed  to  a  high  tempera- 
ture, the  sweat  will  appear  in  all  portions  of  the  body 
with  the  exception  of  the  paralyzed  limb.  The  sweat 
14 


158  GENERAL    ACTION    OF    POISONS. 

centres  are  also  excited  by  carbonic  acid  in  the  blood  ; 
therefore,  drugs  which  cause  dyspnoea  will  tend  to  in- 
crease the  secretion  of  sweat. 

Drugs  may  increase  the  secretion  of  sweat  either  by 
peripheral  stimulation  of  the  secretory  nerves,  or  by 
direct  action  on  the  nerve  centres  ;  as  yet,  we  are  unable 
to  speak  of  action  on  the  centripetal  nerves.  If  a  poison, 
when  injected  into  the  circulation,  produces  sweating  in 
all  the  limbs  of  an  animal  in  whom  one  sciatic  nerve  has 
been  divided,  it  may  be  assumed  that  the  action  is  a 
peripheral  one  ;  if,  however,  the  foot  on  the  side  in  which 
the  sciatic  was  cut  remains  dry,  it  will  be  probable  that 
the  drug  directly  stimulates  the  sweat  centres. 

The  antagonism  of  drugs  may  also  be  treated  ;  thus, 
atropia  will  check  the  secretion  started  up  by  pilocar- 
pine.] 

5.  Lachrymal  Glands. — Increased  secretion  of  tears, 
apart  from  any  direct  irritant  action  on  the  conjunctiva 
or  nasal  mucous  membrane  (reflex  irritation),  is  to  be 
expected  from  those  poisons  which  paralyze  the  vaso-motor 
nerves,  and  can  be  established  by  direct  inspection. 

[We  are  not  yet  familiar  enough  with  the  nervous 
mechanism  governing  this  secretion  to  attempt  to  explain 
the  7nodus  operandi  of  drugs.] 

6.  Lacteal  Glands. — Very  little  is  known  as  to  the  in- 
fluence of  drugs  in  increasing  or  diminishing  the  secretion 
of  milk,  while  it  is  well  known  that  many  poisons  are 
excreted  in  the  milk,  and,  therefore,  give  their  toxic 
properties  to  this  secretion. 

b.  Non  Secretory  Glands. — To  this  group  belong 
the  spleen,  and,  with  the  exclusion  of  its  bile-making 
fuction,  also  the  liver.  As  regards  toxic  action  on  the 
other  glands  of  this  group,  that  is,  the  supra-renal  cap- 
sules, thymus  and  thyroid,  nothing  is  known  ;  while  as  re- 
gards the  lymphatic  glands,  the  most  that  can  be  said  is 
that  when  situated  in  the  neighborhood  of  tissues  in  a 
state  of  inflammation  from  the  action  of  drugs,  they  also 
will  become  inflamed. 


ALTERATIONS    IN    TISSUE    METABOLISM.      159 

The  manifold,  but  still  obscure,  connections  of  the 
liver  with  the  processes  of  nutrition  would  indicate  its 
probably  frequent  implication  in  the  causation  of  the  dis- 
orders produced  by  poisons,  but  still  all  such  disturbances, 
as  for  example,  fatty  degeneration,  with  the  single  excep- 
tion of  those  exhibited  in  the  character  of  the  biliary 
secretion,  are  only  to  be  detected  after  death. 

Studies  as  to  the  possible  effects  of  the  drug  on  the 
glycogen,  or  possibly  the  sugar,  of  the  liver,  should  be 
made  immediately  after  death.  The  liver  must  be  thrown 
instantly  after  death,  after  chopping  up  rapidly  into  a 
few  pieces,  into  a  large  quantity  of  boiling  water,  pre- 
pared beforehand,  and  it  can  then,  while  in  the  water,  be 
either  chopped  into  fine  pieces  or  rubbed  up  into  a  pulp; 
it  is  then  to  be  faintly  acidulated  and  filtered,  and  the 
filtrate  precipitated  with  iodide  of  mercury  and  potassium 
solution  and  hydrochloric  acid,*  and  after  removal  of 
the  precipitate,  the  glycogen  precipitated  with  alcohol. 
The  sugar  can  also  be  determined  in  the  first  filtrate  by 
Tromraer's  test. 

[Changes  in  the  circulation  of  the  spleen  may  be 
studied  by  Roy's  method.  (See  Kidney.)  The  method 
described  for  determining  the  character  of  the  circulation 
in  the  case  of  the  excised  kidney  is  also  applicable  to  the 
liver.] 


Section  V.— Alterations  in  Tissue  Metabolism. 

All  poisons  which  disturb  the  normal  digestive  pro 
cesses,  produce,  when  the  condition  of  poisoning  is  long 
continued,  changes  in  nutrition  analogous  to  those  occur- 
ring in  prolonged  fasting  or  with  insufficient  food  ;  that 
is,  loss  of  weight,  absorption  of  adipose  tissue,  paleness 
of  the  skin  and  mucous  membranes,  loss  of  strength,  and 
in  severe  cases,  death  ;    in  growing  organisms,  growth 

1  Briicke,  Weiner  Acad.  Sitzgsber.  Math.  Natiirw.  CI.  2.  Abth. 
Ixiii.  1871,  Feb.  3. 


1(J0  GENERAL    ACTION    OF    POISONS. 

ceases ;  the  generative  function  is  suspended,  and  in  the 
pregnant  condition  abortion  may  occur.  Similar  results 
in  the  nutritive  functions  may  also  be  caused  in  cases  of 
chronic  poisoning  without  any  clear  disturbance  of  diges- 
tion being  detectable. 

In  addition  to  these  general  disturbances,  single  nutri- 
tive functions  may  be  interfered  with  as  a  consequence 
of  the  action  of  poisons ;  from  the  uncertainty  sur- 
rounding our  knowledge  of  the  pliysiology  of  nutrition, 
many  of  these  cannot  be  explained,  and  we  will  here  only 
allude  to  the  best  known. 

1.  Energy  of  the  Animal  Oxidizing  Processes. — 
The  energy  of  the  oxidizing  processes  occurring  in  the  ani- 
mal economy  is  estimated  either  by  measuring  the  quantity 
of  oxygen  consumed  or  of  the  two  principal  products  of 
oxidation,  carbonic  acid  and  urea.  For  the  estimation 
of  these  gases  the  methods  have  already  been  given, 
while  urea  may  be  estimated  by  Liebig's  method  of  titra- 
tion ;  on  account  of  unavoidable  errors,  however,  con- 
nected with  this  method,  it  is  better  to  estimate  the  total 
quantity  of  nitrogen  in  the  urine  and  feces. ^ 

An  increase  of  oxidation  processes,  as  occurs  in  fever, 
may,  also,  very  probably,  occur  in  toxic  fevers.  On  the 
other  hand,  certain  substances,  such  as  arsenic,  can 
diminish  the  excretion  of  the  products  of  oxidation ;  for 
none  of  these  can  any  clear  explanation  be  given. 

As  general  effects  of  toxic  changes  in  these  processes 
of  oxidation  we  may  have,  when  increased,  elevation  of 
temperature,  rapid  emaciation,  and  loss  of  strength  ; 
when  decreased,  reduction  of  temperature,  deposit  of  fat 
and  excretion  of  sugar  in  the  urine.  The  increase  of 
temperature  in  the  cases  of  toxic  fever  may,  as  in  ordi- 
nary fever,  depend  upon  other  causes  than  increased  oxi- 
dation. On  the  other  hand,  the  deposit  of  fat  and  the 
excretion  of  sugar  is  not  constantly  associated  with  di- 
minished oxidation,  but  may  depend  upon  other  causes. 

*  Segen,  Zeit.  f.  Analyt.  Cheinie,  1864,  p.  155. 


ALTERATIONS    IN    TISSUE    METABOLISM.      161 

2.  Deposit  of  Fat  in  the  Body. — Chronic  poisoning 
with  many  substances  causes  an  increase  in  the  normal 
amounts  of  adipose  tissue  in  the  body  (in  the  subcutane- 
ous tissue,  peritoneum  and  pericardium),  and,  in  addi- 
tion, fatty  degeneration  of  various  organs,  especially  the 
muscles  and  certain  glands,  such  as  the  liver  and  kidneys; 
the  latter  can  also  undergo  acute  fatty  degeneration  from 
the  action  of  certain  poisons  when  continued  only  for  a 
few  days,  or  even  according  to  some  authors,  for  a  few 
hours.  Deposit  of  fat,  with  the  exception  of  increased 
panniculus  adiposus,  can  only  be  recognized  after  death. 
The  cause  of  such  changes  is  entirely  unknown,  and 
probably  varies  in  different  cases  ;  diminution  of  the 
general  oxidation  processes  and  inflammatory  irritation 
of  the  fatty  parenchyma  have  been  advanced  as  possible 
grounds,  but  no  sufficient  proof  of  their  causative  action 
has  been  given.  General  muscular  weakness  will  follow 
fatty  degeneration  of  the  muscles,  and  when  occurring  in 
the  heart  the  pulse  will  be  weakened  and  life  endangered 
not  only  in  this  way,  but  also  by  the  possibility  of  rup- 
ture of  the  heart. 

3.  Diabetes. — A  number  of  poisons  cause  the  excre- 
tion of  sugar  in  the  urine,  a  condition  which  can  be  easily 
recognized  by  Troramer's  test.  Either  an  increased 
sugar  formation  in  the  liver,  or  a  decreased  consumption 
of  sugar  in  the  system  will  cause  diabetes.  As  the 
latter  state  of  affairs  implies  diminished  oxidation,  the 
presence  of  diabetes  is  a  symptom  of  this  derangement 
of  the  general  nutritive  functions,  and  may  be  caused  by 
any  poison  which  interferes  with  respiration,  or  even, 
though  in  both  cases  inconstantly,  by  mechanical  ob- 
struction to  respiration.^  One  of  the  most  remarkable 
forms  of  toxic  diabetes,  that  which  occurs  in  curare 
poisoning,  cannot  be  explained  in  either  of  these  ways, 
since  curare  does  not  cause  an  increase  either  of  gly- 
cogen or  sugar  in  the  liver,  nor  can  any  reason  be  given 
why  artificial  respiration,  or  muscular  contractions  pro- 

1  See  literature  of  this  subject  in  Arch.  f.  Path.  Anat.,  xlii.  1. 
14* 


162  GENERAL    ACTION    OF    POISONS. 

duced  by  direct  stimulation  should  in  curare  poisoning 
interfere  with  the  destruction  of  sugar. ^  From  the 
physiological  point  of  view,  the  results,  of  Pavy,  Tscher- 
inoff,  Dock,  and  others  have  necessitated  a  modification 
of  the  usual  explanation  of  diabetes,  so  as  to  render  the 
view  probable  in  toxic  diabetes,  that  there  is  either  some 
change  produced  in  the  functions  of  the  liver,  whereby 
the  change  of  sugar  into  glycogen  is  prevented,  or  by 
which  the  glycogen  in  the  liver  and  also  in  the  muscles 
is  turned  into  sugar.  It  is,  moreover,  conceivable  that 
toxic  diabetes  may  be  due  to  some  process  without  any 
physiological  analogue,  whereby  sugar  is  formed  from 
some  other  sources  than  those  recognized  as  physiolo- 
gical. For  example,  such  a  result  might  exist  as  a 
special  action  on  certain  tissues,  either  directly  produced 
or  indirectly  through  circulatory  or  respiratory  changes. 
Indeed,  it  is  not  improbable  that  poisons  which  cause 
vascular  paralysis  may  produce  diabetes  by  modifying 
the  blood  supply  of  the  liver. 

When,  therefore,  it  has  been  established  that  a  certain 
drug  causes  diabetes,  the  animal  must  be  allowed  to  fast 
for  several  days,  so  as  to  free  the  liver  from  its  store  of 
glycogen,  and  the  poison  then  given ;  if  in  such  a  case 
diabetes  still  is  found,  it  may  be  concluded  that  it  was 
not  entirely  due  to  the  modifications  of  the  glycogen  of 
the  liver.  Then  it  must,  also,  in  all  cases,  be  established 
whether  the  poison  paralyzes  the  vascular  system. 

A  thorough  study  with  prospect  of  positive  results 
will  in  many  cases  be  impossible.. 


Section  VI. — Alterations  in  the  Reproductive 
Functions. 

The  general  sexual  functions,  the  secretion  of  sper- 
matozoa in  the  male,  and  ovulation  and  menstruation  in 
the  female,  are  so  intimately  connected  with  the  general 

J  Winqgradoff,  Arch.  f.  Path.  Anat.,  xxvii.  533. 


ALTERATIONS    IN    REPRODUCTIVE  FUNCTIONS.       163 

nutritive  condition  of  the  system,  that  no  profound  or 
long-continued  departures  from  normal  nutritive  activity 
can  be  caused  without  being  reflected  on  the  generative 
functions.  In  addition  to  this,  many  drugs  act  directly 
on  the  sexual  apparatus,  either  increasing  or  depressing 
its  activity.  As  yet  experimental  pharmacology  has  only 
dealt  with  the  action  of  drugs  on  uterine  contractions. 

Poisons  which  cause  contraction  of  the  uterus  may, 
during  pregnancy,  induce  abortion,  and  during  labor  ac- 
celerate delivery.  Abortion,  following  the  administra- 
tion of  a  drug,  cannot  invariably  be  referred  to  the 
direct  toxic  induction  of  uterine  contractions,  since  the 
nutritive  changes  alluded  to  above  may  also  induce  abor- 
tion "  from  weakness,"  or  abortion  may  result  from  the 
death  of  the  foetus  through  absorption  of  the  poison  from 
the  maternal  system. 

In  the  case  of  every  poison  which  induces  uterine 
contractions  (a  condition  which  can  be  best  studied  by 
opening  the  abdomen  in  young  non-pregnant  rabbits,  in 
which  the  uterus  is  normally  motionless),  it  must  be 
determined  whether  the  poison  acts  directly  or  reflexly 
on  the  motor  apparatus,  and  in  the  former  case,  whether 
the  uterine  muscles,  nerves,  or  centres  are  stimulated ; 
and  as  the  uterus  contains  several  centres,  with  which 
one  the  action  is  concerned :  and,  finally,  whether  the 
uterine  centres  are  directly  stimulated  by  the  poison  or 
reflexly  through  increased  venosity  of  the  blood.  An 
analogous  series  of  inquiries  will  arise  in  the  case  of 
drugs  paralyzing  the  uterus,  a  condition  which  offers 
even  less  hope  of  thorough  elucidation  than  in  the  case 
of  uterine  stimulants. 

[It  is  generally  admitted  that  toxic  uterine  contrac- 
tions are,  in  the  majority  of  cases,  due  to  contractions  of 
the  arterioles,  either  supplying  the  uterus  or  the  brain  ; 
hence  the  uterine  and  cerebral  and  spinal  nervous  mecha- 
nisms are  only  indirectly  stimulated  by  the  drugs,  the 
effects  being  primarily  due  to  changes  in  blood-supply. 
When  contractions  fail  after  section  of  the  cord  after  the 
xidministration  of  a  poison  which  otherwise  is  capable  of 


164  GENERAL    ACTION    OF    POISONS. 

inducing  uterine  contraction,  it  may  be  assumed  that  they 
were  produced  by  circulatory  changes  in  the  brain.] 

The  action  of  drugs  on  the  development  of  the  egg  has 
not  been  studied,  though  it  is  known  that  poisons,  in  the 
case  of  birds,  may  pass  into  the  ovum  while  still  within 
the  ovary ;  or  into  the  developing  egg  or  embryo,  by 
means  of  the  placenta,  while  within  the  cavity  of  the 
uterus. 


Section  VII. — Alterations  in  Temperature. 

The  alterations  of  body  temperature,  frequently  pro- 
duced by  poisons,  may  depend  upon  either  a  modification 
of  heat-production  or  of  heat-loss  ;  in  both  cases  the 
normal  regulating  processes  must  be  interfered  with. 
Increased  loss  of  heat  may  occur  when  the  cutaneous 
bloodvessels  are  paralyzed,  or  diminished  loss  of  heat 
when  contracted  ;  in  nearly  all  other  cases  it  will  be 
found  that  the  heat-producing  functions  are  at  fault. 
The  muscles  are  the  organs  mainly  concerned  in  heat- 
production  ;  so  when  a  poison  causes  convulsions  the 
temperature  will  usually  be  raised  by  increased  heat- 
production,  and  muscular  paralysis  will  lead  to  lessened 
heat-production,  with  the  appropriate  changes  in  the  body 
temperature  ;  unless  the  losses  of  heat  also  suffer  some 
disturbance  which  can  nullify  these  results,  and  maintain 
a  normal  standard. 

[For  methods  of  making  calorimetric  studies,  see  San- 
derson's Hand  Book  to  the  Physiological  Laboratory,  or 
Prof.  H.  C.  Wood's  Memoir  on  Fever.] 


Section  VIII. — Action  on  the  Muscles. 

Paralysis  and  abnormal  muscular  contractions  are 
often  produced  by  the  action  of  poisons ;  whether  these 
depend  upon  direct  action  on  the  muscle,  or  through  the 
medium  of  the  nervous  system,  can  readily  be  determined 


ACTION    ON    THE    MUSCLES.  165 

by  simple  experiments.  In  paralysis  it  is  only  neces- 
sary to  stimulate  the  muscles  directly,  and  if  contraction 
occurs,  the  trouble  is  proved  to  be  in  the  nervous  sys- 
tem ;  in  convulsions  a  positive  result  may  be  obtained  by 
section  of  the  nerve  of  any  selected  group  of  muscles  ; 
for  if  the  convulsions  persist,  they  must  be  due  to  some 
cause  acting  either  directly  on  the  muscular  fibres  or  on 
the  intra-muscular  nerve  endings.  In  order  to  discrimi- 
nate between  these  two  possibilities,  the  animal  must  be 
poisoned  with  curare,  w^hich  paralyzes  the  intra-muscu 
lar  nerve  fibres  (of  course  in  such  cases  in  warm-blooded 
animals  artificial  respiration  must  be  maintained),  before 
the  administration  of  the  drug  under  study  ;  if,  under 
such  circumstances,  the  convulsions  do  not  appear,  it 
may  be  confidently  concluded  that  the  intra-muscular 
nerve  fibres  were  the  seat  of  the  stimulation,  while  their 
appearance  would  indicate  action  on  the  muscular  fibre. 
Indeed,  as  will  be  shown  presently,  it  can  often  be  de- 
termined from  the  general  character  of  the  convulsions 
whether  they  are  of  central  or  peripheral  origin,  and  in 
cold-blooded  animals  the  methods  of  exclusion  mentioned 
on  page  32  may  be  employed.  In  warm-blooded  ani- 
mals, a  poison  which  produces  its  results  through  direct 
action  on  the  muscles  or  peripheral  nervous  system, 
whether  stimulant  or  depressing,  will  first  produce  its 
characteristic  action  after  hypodermic-  injection  in  the 
parts  with  which  the  poison  comes  in  contact,  so  showing 
its  peripheral  mode  of  action.  More  extended  experi- 
ments as  to  the  changes  in  irritability  of  muscles,  as  well 
as  alterations  in  energy  and  time  of  contraction,  are  best 
made  on  the  excised  frog's  muscle,  in  the  manner  de- 
scribed on  page  31. 

In  many  cases  poisons  will  cause  alterations  in  the 
normal  positions  of  the  limbs,  from  paralysis  or  spasm 
of  individual  muscles. 

Under  this  heading  may  also  be  considered  the  action 
of  drugs  on  the  pupil. 

1.  Action  on  the  Pupil. — [The  size  of  the  pupil  de- 
pends upon  the  degree  of  contraction  of  the  two  antago- 


166  GENERAL    ACTION    OF    POISONS. 

nistic  muscular  S3^stems  of  the  iris,  the  circular  constric- 
tor fibres,  supplied  by  the  oculo-motor  nerve,  and  the 
radiating  dilator  fibres,  supplied  by  nerv^es  derived  from 
the  sympathetic  system.  Both  sets  of  nerves  are  nor- 
mally in  a  state  of  constant  excitation,  since  if  the  oculo- 
motor is  divided  or  paralyzed  the  pupil  dilates,  and  if  the 
sympathetic  is  divided  in  the  neck,  or  its  terminal  fibres 
paralyzed,  the  pupil  contracts.  In  addition  to  changes 
in  the  size  of  the  pupil  dependent  upon  direct  irritation  or 
paralysis  of  these  nerves,  the  pupil  may  be  contracted, 
(1)  reflexly  through  the  oculo-motor  nerve  by  stimuli 
applied  to  the  optic  nerve,  which  thus  acts  as  the  affer- 
ent nerve;  (2)  when  the  eye  is  accommodated  for  near 
vision  ;  (3)  when  the  eyeballs  are  rotated  inwards.  The 
pupils  are  dilated,  (1)  during  dyspnoea  through  irritation 
of  the  cilio-spinal  centre,  the  irritation  being  transmitted 
through  the  sympathetic  nerve  to  the  dilator  fibres  of  the 
iris  ;  this  dilatation  ceases  when  the  dyspnoea  passes  into 
asphyxia,  and  does  not  occur  after  division  of  the  cervi- 
cal sympathetics  ;  its  production  in  this  manner  by  drugs 
can  be  therefore  readily  excluded  ;  (2)  during  powerful 
irritation  of  sensory  nerves ;  and  (8)  during  violent 
muscular  movements. 

In  addition,  still,  to  these  central  mechanisms,  there 
appears  to  be  present  in  the  eye  itself  some  apparatus 
by  which  dilatation  or  contraction  may  be  produced : 
for  when  the  third  nerve  is  divided,  and  the  pupil  dilated 
under  the  full  influence  of  the  sympathetic  nerve,  the 
instillation  of  atropia  still  further  dilates  the  pupil  ;  and 
when  physostigmine,  under  the  same  circumstances,  is  in- 
troduced into  the  eye  or  system,  the  pupil  is  contracted. 
It  is  probable,  therefore,  that  the  dilator  and  constrictor 
nerves  of  the  iris  produce  changes  in  the  size  of  the 
pupil  by  the  transmission  of  stimuli  to  some  local  appar- 
atus seated  in  the  eye  itself. 

To  determine  the  character  of  the  action  of  drugs  on  the 
pupil,  the  effects  of  both  local  application  and  venous  in- 
jection should  be  studied :  the  positive  decision,  however, 
as  to  the  precise  means  by  which  the  toxic  mydriasis  or 


ACTION    ON    THE    MUSCLES.  167 

myosis,  as  the  case  may  be,  is  produced,  is  a  matter  of  the 
greatest  difficulty,  the  modus  operandi  oi  Qvan  such  well- 
known  drugs  as  atropia  and  eserine  being  still  a  matter 
of  controversy.  At  the  outset,  reflex  causes  of  change 
in  the  pupil,  such  as  are  produced  by  dyspnoea,  etc., 
must  be  excluded.  The  question  will  then  arise  as  to 
whether  dilatation  is  due  to  paralysis  of  the  oculo-mo- 
tor  or  excitation  of  the  sympathetic,  or  both,  or  whether 
the  action  is  purely  local  on  the  eye.  Constriction  of 
the  pupil  will  of  course  be  due  to  the  opposite  condi- 
tions. 

Let  us  first  assume  that  we  are  dealino;  with  a  druo; 
which  produces  dilatation  of  the  pupil ;  the  first  point 
then  to  determine  is  whether  the  sphincter  muscle  of  the 
iris  still  preserves  its  capability  of  contraction.  This 
may  be  determined  by  the  method  employed  by  Bern- 
stein and  Dogiel  ;^  four  wires  are  connected  with  the 
poles  of  the  secondary  coil  of  an  induction  apparatus  and 
their  free  ends  (arranged  in  the  form  of  a  square,  simi- 
lar poles  occupying  diagonal  corners)  placed  on  the 
inner  edge  of  the  iris.  By  this  means  the  circular  fibres 
of  the  iris  will  be  stimulated,  and  if  they  retain  their 
normal  functions,  the  pupil  will  contract.  If  no  change 
occurs  in  the  size  of  the  pupil  w^hen  this  experiment  is 
properly  performed,  it  may  be  assumed  that  the  drug 
produces  dilatation  of  the  pupil  by  paralysis  of  the  sphinc- 
ter muscle,  and  no  other  experiments  need'be  made  ;  in 
the  great  majority  of  cases,  however,  the  pupil  will  still 
contract,  and  it  is  then  necessary  to  determine  whether 
the  dilatation  is  due  to  paralysis  of  the  oculo-motor 
nerve,  or  spasm  of  the  dilator  muscle. 

In  order  to  test  the  irritability  of  the  oculomotor 
nerve,  it  is  necessary  to  open  the  cranial  cavity  and  re- 
move the  cerebral  hemispheres. 

To  make  this  experiment,  the  drug  is  first  instilled  into 
the  conjunctival  sac  in  a  dog  or  rabbit,  and  the  change 

1  Verhandl.  d.  nat.  Med.  Vereins  zu  Heidelberg,    iv.  28,  Her- 
mann. 


168  GENERAL    ACTION    OF    POISONS. 

in  size  of  the  pupil  noted  in  millimeters.  Tracheotomy 
is  then  performed,  artificial  respiration  maintained,  and 
both  carotids  ligated  in  the  neck  ;  the  next  step  is  to 
remove  the  vault  of  the  cranium  with  bone  forceps  and 
to  elevate  the  cerebral  lobes  with  a  spatula  ;  after  divi- 
sion of  the  olfactory  and  optic  nerves,  the  oculo-motor 
nerves  may  be  found  on  the  sella  turcica.  The  caver- 
nous sinus  must  be  carefully  avoided :  bleeding  from 
the  posterior  cerebral  arteries  may  be  Controlled  by 
slight  pressure  with  a  moist  sponge.  The  oculo-motor 
nerve  on  the  side  of  the  eye  in  which  the  poison  was 
instilled,  is  then  to  be  divided  as  near  the  brain  as  possi- 
ble and  the  peripheral  end  placed  on  the  electrodes  of  an 
induction  coil  and  stimulated ;  if  no  contraction  ot  the 
pupil  is  produced  thereby,  it  may  be  concluded  that  the 
terminal  fibres  of  the  nerve  supplying  the  constrictor 
muscle  of  the  iris  are  paralyzed.  (For  convenience  of 
measurement  of  the  size  of  the  pupil,  it  is  advisable  to 
slit  up  the  external  commissure  and  draw  down  the  lower 
eyelid  by  a  weighted  thread  passed  through  it  and  the 
nictitating  membrane.) 

Should  the  pupil  contract  on  stimulation,  it  remains 
then  to  be  seen  whether  the  dilatation  is  due  to  stimu- 
lant action  on  the  dilator  apparatus  ;  and  even  when 
stimulation  fails  to  narrow  the  pupil,  it  is  well  to  see 
whether  there  is  an  associated  spasm  of  the  radiating 
fibres  of  the  iris.  This  may  be  determined,  as  suggested 
by  Bernstein  and  Dogiel,  by  placing  the  two  electrodes 
of  the  induction  apparatus  on  the  side  of  the  cornea ;  if 
the  pupil  dilates  still  further,  the  integrity  of  the  radiat- 
ing muscles  is  proved,  while  the  functional  condition  of 
their  nerve  supply  is  tested  by  stimulation  of  the  cer- 
vical sympathetic. 

The  above  experiments  would  serve  to  give  a  some- 
what decisive  answer  to  the  question  as  to  the  modus 
operandi  of  mydriatics  were  it  not  known  that  many 
drugs,  such  as  atropia,  are  capable  of  producing  dilata- 
tion of  the  pupil  in  the  excised  eye  of  the  frog,  where  of 
course,  there  can  be  no  question  as  to  paralysis  of  the 


ACTION    ON    THE    NERVOUS    SYSTEM.  169 

opulo-motor  nerve  endings  which  have  been  already  sepa- 
rated from  their  nerve  centre  ;  and  even  after  division 
of  the  oculo-motor  nerve  (for  methods  see  Cyon  31ethodik, 
p.  510,  or  Bernard,  PJiysiologie  Exp.  de  la  Sy§.  Nerv.) 
atropia  is  capable  of  still  further  dilating  the  pupil.  In 
view  of  such  facts  it  is  necessary  to  assume  the  existence 
of  peripheral  ganglia  in  the  iris  itself,  where  indeed 
nerve-cells  have  been  found  in  abundance. 

In  the  case  of  drugs  which  produce  contraction  of  the 
pupil  (myosis),  the  probability  will  lie  in  favor  of  a 
spasm  of  the  sphincter  muscle  when  there  is  also  found 
by  the  ophthalmoscope  to  be  spasm  of  the  muscles  of 
accommodation.  Additional  evidence  will  be  added  to 
this  view  when  the  drug  produces  a  higher  degree  of 
contraction  than  follows  section  of  the  sympathetic,  when 
atropia  is  capable  of  overcoming  the  myosis  produced 
by  the  drug,  and  when  irritation  of  the  sympathetic,  in 
an  eye  so  treated,  is  capable  of  still  further  dilating  the 
pupil.] 


Section  IX.— Action  on  the  Nervous  System. 

In  previous  chapters  reference  has  already  been 
made  to  several  derangements  of  the  nervous  system 
produced  by  the  action  of  poisons,  but  it  still  seems 
advisable  to  again  group  them  under  their  appropriate 
heading. 

A.  Action  on  the  Organs  of  Conduction. — Toxic 
action  on  the  nerve  trunks  occurs  much  more  seldom 
than  on  the  nerve  terminations.  This  may  probably  be 
due  to  the  limited  supply  of  blood  which  these  portions 
of  the  nervous  system  normally  receive,  since  they  are 
equally  sensitive  to  direct  action  with  solutions  of  the 
poison  (see  p.  50). 

In  the  case  of  many  poisons  which  act  primarily  on 
the  nerve-endings,  particularly  in  vascular  organs  such 
15 


170  GENERAL    ACTION    OF    POISONS. 

as  the  muscles,  the  functional  disturbance  gradually 
spreads  up  the  trunk  of  the  nerve. 

The  functional  disturbances  produced  in  the  organs 
of  conduction  by  the  action  of  poisons,  may  be  of  two 
kinds  :  first,  modifications  in  the  normal  nervous  stimuli  ; 
second,  in  abnormal  stimuli.  The  first  of  these  condi- 
tions may  be  manifested  in  diminution  or  abolition  of 
irritability  (loss  of  the  power  of  conducting  impressions), 
or  in  exaltation  of  irritability  or  in  abnormal  persistence 
of  excitation.  Loss  of  the  power  of  conduction  in  nerve 
trunks  is  disclosed  ^y  the  absence  of  the  usual  result 
of  stimulation,  as,  for  example,  the  non-appearance  of 
vascular  contraction  after  normal,  central,  or  artificial 
stimulation  of  a  motor  nerve,  and  in  the  case  of  sensory 
nerves,  in  abolition  of  sensibility  in  the  surfaces  on  which 
these  nerves  are  distributed. 

[It  should  be  noted  that  while  but  few  drugs  com- 
pletely  destroy  the  power  in  nerves  of  conducting  im- 
pressions, many  poisons  will  depress  the  irritability  of 
nerves  below  normal.  When,  therefore,  it  is  found  that 
after  death  both  the  muscles  and  nerves  are  capable  of 
responding  to  stimulation,  it  should  then  be  tested 
whether  there  has  been  any  alteration  in  the  degree  of 
irritability.  To  accomplish  this,  the  vessel  in  one  hind 
leg  of  a  frog  is  ligated,  and  the  poison  injected  under 
the  skin  of  the  back.  When  the  eftects  of  the  poison 
are  clearly  marked,  the  sciatics  are  laid  bare,  and  the 
strength  of  current  which  is  necessary  to  produce  con- 
traction determined  for  each  limb  :  the  irritability  of  the 
poisoned  and  non-poisoned  sciatics  can  be  thus  com- 
pared.] 

Increase  (accumulation)  of  the  irritant  action  during 
its  conduction  along  the  nerve,  has  never  been  observed 
as  a  result  of  toxic  action  ;  but,  on  the  other  hand,  ab- 
normal persistence  of  stimulation,  such  as  the  production 
of  tetanus  or  prolonged  muscular  contraction,  as  a 
result  of  a  single  stimulus,  has  been  described  in  numer- 
ous instances.  Abnormal  irritations  evoke  convulsive 
muscular  contractions  where  the  motor  nerves  are  con- 


ACTION    ON    THE    NERVOUS    SYSTEM.  171 

cerned,  and  painful  or  abnormal  sensations,  or  subjec- 
tive sensations  for  the  nerves  of  special  sense,  when  the 
stimulus  affects  a  sensory  nerve. 

The  first  point  to  be  determined  in  the  study  of  toxic 
effects  of  the  above  nature  (convulsions,  paralysis,  etc.), 
is  whether  they  are  due  to  alterations  in  the  organs  of 
conduction.  In  the  case  of  paralysis,  this  is  readily 
determined  by  separate  stimulation  of  nerve  and  muscle. 
If  the  latter  (direct  stimulation)  produces  a  muscular 
contraction,  while  indirect  stimulation  does  not,  it  may 
be  concluded  that  there  is  some  interruption  in  the  con- 
ductivity of  the  nerve,  and  if  the  stimulus  remains  in- 
effective, even  when  applied  to  the  nerve  immediately 
before  its  entrance  into  the  muscles,  it  would  indicate 
that  the  loss  of  function  lies  in  the  intra-muscular  portions. 
To  decide  in  such  a  case  whether  the  remainder  of  the 
nerve  is  implicated,  the  muscle  may  be  excluded  from 
the  poisoned  circulation  in  the  manner  described  on  page 
32,  or  galvanic  stimuli  employed.  If  convulsions  are 
produced,  their  nature  will  give  some  general  idea  as  to 
their  origin.  Convulsions  of  central  origin  throw  the 
entire  muscle,  and  usually  entire  groups  of  muscles,  into 
co-ordinated  contractions  ;  on  the  other  hand,  convulsions 
originating  in  the  nerves,  or  in  their  intra-muscular 
endings,  usually  implicate  different  muscular  fibres  at 
different  times,  and  with  different  degrees  of  vigor,  pro- 
ducing the  so-called  "fibrillar  contractions." 

[Even  fibrillar  contractions,  however,  may  be  of  cen- 
tral origin,  since  Von  Anrep  has  found  that  after  injec- 
tions of  nicotine  they  occur  in  limbs  protected  from 
local  action  of  the  poison  by  ligation  of,  their  blood- 
vessels.] 

Above  all,  however,  it  should  be  remarked  that  such 
contractions  persist  after  separation  of  the  nerves  from 
the  central  organs,  a  procedure  which  will  interrupt  or 
prevent  the  appearance  of  convulsions  of  central  origin. 
Finally,  convulsions  due  to  action  on  the  organs  of  con- 
duction do  not  appear  in  limbs  which  have  been  protected 
from  access   of  the   poison  by  ligation  of  their  blood- 


liZ  GENERAL    ACTION    OF    POISONS. 

vessels,  while  convulsions  of  central  ori,2;in  affect  equally 
all  members,  whether  connected  with  the  circulation  or 
not,  provided  only  that  the  nerves  remain  intact.  .  [Con- 
vulsions of  cerebral  origin  disappear  after  removal  of 
the  medulla,  while  convulsions  of  spinal  origin  persist.] 

B.  Action  on  the  Peripheral  Nerve  Endings. — 
Sufficient  has  already  been  said  on  page  50,  as  to  the 
action  of  poisons  on  the  peripheral  terminal  fibres  of 
motor  nerves ;  at  present  we  are  only  concerned  with 
the  peripheral  endings  of  centripetal  nerves.  These 
organs  are  liable  to  toxic  action  whenever  a  poison, 
either  by  direct  contact  or  by  means  of  the  circulation, 
is  brought  to  the  organs  in  which  they  are  situated. 
The  toxic  influence  may  be  manifested  either  by  excita- 
tion or  paralysis,  or  occasionally  the  latter  condition 
may,  as  a  result  of  the  same  drug,  follow  a  condition  of 
increased  irritability.  The  consequences  of  stimulation 
of  the  sensory  nerves  may  be  evidenced  either  by  various 
abnormal  sensations  (subjective  sensations  for  the  nerves 
of  special  sense),  or  in  modification  of  reflexes,  such  as 
secretion  of  tears,  saliva,  or  in  vomiting.  Paralysis  of 
these  organs  is  followed  by  insensibility  and  loss  of 
reflexes. 

Such  disturbances  of  function  can  be  readily  localized 
in  either  the  central  or  peripheral  nervous  system. 
Symptoms  of  irritation  which  disappear  on  section  of  the 
nerve  as  near  the  periphery  as  possible,  and  symptoms 
of  paralysis  which  are  not  evident  when  the  stimulus  is 
applied  directly  to  the  nerve-trunk,  must  be  due  to  the 
action  of  the  poison  on  the  peripheral  nervous  apparatus. 
But,  unfortunately,  the  only  animals  on  which  such  de- 
cisive experiments  can  be  made  are  the  very  animals 
which  are  most  unsuitable  for  the  study  of  the  points  in 
question  ;  therefore  we  are  practically  restricted,  as  far 
as  accurate  results  are  concerned,  to  such  evidence  of 
the  state  of  the  conductive  sensory  function  as  is  found 
in  the  character  of  the  reflexes,  and  in  these  experiments 
it  is  almost  impossible  to  distinguish  between  results  due 


ACTION    ON    THE    NERVOUS    SYSTEM.  17B 

to  action  on  the  peripheral,  conducting,  or  central  sen- 
sory organs. 

The  same  class  of  experiments  may  be  made  as  has 
been  given  for  the  study  of  the  action  of  poisons  on 
the  motor  nerves.  When  the  action  is  localized  to  the 
point  of  application  of  the  poison,  or  can  be  excluded 
from  a  limb  by  ligation  of  its  bloodvessels,  or  when  it 
appears  more  markedly  and  rapidly  in  an  organ  in 
whose  arteries  it  has  been  injected,  it  indicates  that  the 
principal  action  is  on  the  peripheral  organs.  If  one 
possessed  a  means  of  paralyzing  the  peripheral  endings 
of  centripetal  nerves,  as  curare  paralyzes  the  centrifugal, 
all  phenomena  depending  on  irritation  of  these  structures 
must  be  absent  after  the  administration  of  such  a  poison, 
and  the  symptoms  which  appear  before  its  administration, 
and  fail  to  appear  after  it,  must  be  due  to  stimulant 
action  of  the  peripheral  sensory  apparatus ;  unfortu- 
nately, no  such  drug  has  yet  been  discovered. 

[Various  methods  have  been  proposed  for  investi- 
gating the  condition  of  the  centripetal  nerves  ;  all  are, 
however,  open  to  objection.  Probably  the  best  method 
is  to  ligate  the  bloodvessels  in  one  limb  of  a  frog,  and 
then  inject  the  poison  into  the  dorsal  lymph-sac  ;  after 
the  effects  of  the  poison  have  been  developed,  compari- 
sons can  be  made  between  the  irritability  of  the  central 
ends  of  the  sciatic  nerves ;  that  is,  whether  a  stronger 
irritant  is  required  on  the  poisoned  than  on  the  unpoison- 
ous  side  to  produce  reflex  movements.  The  success  of 
this  experiment  will  depend  upon  the  integrity  of  the 
motor  nerves,  for,  if  they  are  paralyzed,  of  course  no 
reflexes  can  be  produced.  In  such  cases  one  hind  limb 
of  a  frog  may  be  partially  amputated,  leaving  only  the 
sciatic  nerve  intact,  and  the  poison  then  injected  into 
the  amputated  limb,  and  the  capability  of  transmitting 
impressions  tested  by  comparing  the  reflexes  produced 
by  stimulation  of  the  skin  of  each  hind  foot. 

Von  Bezold  proposed  a  method  of  testing  the  irrita- 
bility of  sensory  nerves,  in  which  the  reflex  contractions 
of  a  frog,  feebly  under  the  influence  of  strychnia,  served 

]5* 


174  GENERAL    ACTION    OF    POISONS. 

as  an  index  of  sensory  excitation.  This  method,  as 
modified  by  Pflliger,  consists  in  the  following  :  the  blood- 
vessels are  tied  in  the  lower  extremities  of  a  frog,  and 
these  limbs  then  so  severed  from  the  body  that  their  only 
connections  are  the  sciatic  nerves.  These  nerves  are 
then  kept  constantly  moistened,  one  with  a  solution  of 
phosphate  of  sodium,  and  the  other  with  a  solution  of  the 
drug,  both  solutions  being  of  the  same  degree  of  concen- 
tration. Then  by  irritating  the  central  end  of  each  sci- 
atic on  the  distal  side  of  the  solution,  a  general  idea  can 
be  obtained  as  to  the  action  of  the  drug  on  the  sensory 
nerves.  The  objection  to  this  method  is  the  difficulty  in 
comparing  the  osmotic  equivalents,  under  such  circum- 
stances, of  diiferent  drugs.  In  the  case  of  drugs  which 
have  been  proven  to  be  inactive  on  the  motor  nerves,  the 
first  method  is  the  best,  even  when  the  drug  is  known  to 
mcjdify  the  functions  of  the  spinal  cord.] 

Another  question,  which  also  is  difficult  to  answer 
positively,  is  whether  the  results  above  alluded  to  are 
due  to  specific  action  on  the  nervous  apparatus,  or  to 
some  action  on  the  tissues  in  which  they  are  located,  as 
it  is  well  known  that  every  strong  mechanical  or  chemi- 
cal lesion  of  a  tissue  acts  as  an  irritant  to  the  nerve- 
fibres  of  that  organ.  It  is  only  possible,  however,  to 
express  an  opinion  as  to  this  point  when  the  organ  is  the 
seat  of  gross  anatomical  changes  ;  w4ien  these  are  not  to 
be  detected,  we  must  conclude  that  the  drug  exerts  a 
specific  action  on  the  nerve  endings.  But  even  should 
anatomical  lesions  be  found,  the  possibility  of  a  specific 
action  on  the  nervous  organ  is  by  no  means  excluded ;  for 
these  changes,  depending  upon  disturbances  of  circula- 
tion, leading  to  hypersemia  and  inflammation,  may  them- 
selves be  the  palpable  reflex  result  of  action  on  the 
nervous  system.  A  specific  action  on  the  nervous  system 
may  be  assumed  when  sensory  or  reflex  phenomena 
(pain,, vomiting,  sneezing)  appear  without  any  evident 
change,  or  with  only  tardy  alteration  in  the  tissue  on 
which  the  drug  is  acting.  A  specific  action  can  be  fur- 
ther inferred   when   a    drug    produces  different   results 


ACTION    ON    THE    NERVOUS    SYSTEM.  175 

when  applied  to  different  tissues  of  the  same  general 
functions,  but  with  different  nerve-supplj. 

C.  Action  on  the  Central  Nervous  System. — 
Action  under  the  most  manifold  forms  on  the  nerve 
centres  is  one  of  the  most  frequently  observed  effects  of 
poisons.  As  the  action  on  the  nerve  centres  of  the  heart 
and  intestine  has  been  already  studied,  the  present 
chapter  will  be  confined  to  the  consideration  of  toxic 
action  on  the  brain  and  spinal  cord. 

The  separation  of  the  action  of  poisons  on  the  central 
system  from  that  on  other  organs  is  usually  easily 
attained.  In  a  large  group  of  these  phenomena,  the 
sensory,  no  doubt,  can  arise;  and  further,  irregularity 
in  a  rhythmical  motion  can  only  depend  upon  action  on 
a  nerve  centre,  though  alterations  in  the  frequency  of 
rhythm  can  be  caused  by  action  oh  the  centripetal 
regulating  nerves,  a  possibility  which  is  readily  ex- 
cluded by  section  of  those  nerves.  But  in  many  other 
cases,  the  toxic  phenomena  are  so  manifestly  of  cen- 
tral nervous  origin  that  no  such  control  experiment  is 
necessary.  Co-ordinated  contractions,  such  as  the  move- 
ments of  deglutition;  paralyses  of  muscular  groups  wh6se 
movements  are  governed  by  a  special  nerve  centre,  such 
as  the  muscles  of  respiration;  painful  sensations  or  anaes- 
thesia of  the  entire  skin,  or  of  surfaces  in  no  direct  com- 
munication with  the  point  of  absorption  of  the  poison,  are 
all,  with  great  probability,  to  be  referred  to  specific  ac- 
tion on  the  nerve  centres.  Still,  some  limitation  of  this 
statement  should  be  made  for  the  group  of  motor  pheno- 
mena, since  many  of  the  co-ordinated  muscular  move- 
ments, such  as  deglutition  and  vomiting,  can  also  be  pro- 
duced by  toxic  stimulation  of  certain  peripheral  organs. 

The  cause  of  phenomena  resulting  from  exaltation  of 
function,  such  as  convulsions  or  sensory  phenomena  re- 
sulting from  toxic  action,  can  be  localized  in  the  central 
apparatus  by  section  of  the  nerves  going  to  the  affected 
organs,  when  of  course  the  disappearance  of  the  symp- 
toms would  prove   their  central  origin.     In  certain  co- 


176  GENERAL    ACTION    OF    POISONS. 

ordinated  movements,  the  possible  peripheral  origin  may 
be  excluded  by  section  of  the  appropriate  nerves.  Motor 
and  sensory  paralyses,  whose  general  character  fails  to 
give  any  indication  as  to  their  origin,  must  be  regarded 
as  central  when  the  peripheral  origin  has  been  excluded 
by  the  means  mentioned  in  the  preceding  chapter. 

In  all  toxic  phenomena  whose  central  origin  has  been 
established  by  these  methods,  the  question  arises  as  to 
w^hether  they  are  due  to  direct  specific  action  on  the  cen- 
tre, or  to  indirect  action  through  changes  in  the, blood,  or 
to  local  disturbances  of  circulation  in  the  nerve  centres  by 
action  of  the  drug  on  the  heart  or  vessels;  since  any  one 
of  these  departures  from  the  normal  relations  will  exert  a 
profound  influence  on  the  nerve  centres.  Such  points  may 
be  readily  investigated  in  the  frog;  for  if  the  same  class 
of  symptoms  appear  in  the  frog  as  in  the  warm-blooded 
animals  they  can  be  safely  attributed  to  specific  action 
on  the  nerve  centres,  since  we  have  found  that  the  func- 
tions of  the  nervous  system  are  in  cold-blooded  animals 
independent  of  the  state  of  the  circulation.  Should, 
however,  the  symptoms  of  poisoning  vary  in  the  two 
classes  of  animals,  it  cannot  be  concluded  Avith  the  same 
degree  of  confidence,  though  the  conclusion  will  be  cor- 
rect in  many  cases,  that  in  the  higher  animals  they  are 
due  to  indirect  action  on  the  nervous  system,  since  the 
results  may  be  attributable  to  different  modes  of  action 
on  the  different  species.  The  supposition  as  to  indirect 
action  will  be  greatly  confirmed  when  it  is  known  that 
the  drug  in  question  produces  alteration  in  the  function 
of  the  heart,  respiratory  apparatus  or  blood,  it  only  being 
necessary  to  determine  which  group  of  phenomena  first 
appears.  In  certain  cases  control  experiments  may  be 
made  in  preventing,  or  compensating  for  the  respiratory 
or  circulatory  action  of  the  poison;  for  example,  changes 
in  the  respiratory  gases  of  the  blood  may  be  prevented 
by  artificial  respiration  ;  contraction  of  the  bloodvessels, 
by  large  doses  of  curare.  If,  after  experiments  of  this 
nature,  the   same   symptoms  do  not   result,  it   may  be 


ACTION    ON    THE    NERVOUS    SYSTEM.  177 

positively  concluded    that   they  are  due  to  an  indirect 
nervous  action  only. 

1.  Interference  with  the  Automatic  Func- 
tions.— The  automatic  functions  of  the  medulla  oblon- 
gata, especially  the  innervation  of  the  respiratory  move- 
ments, the  regulation  of  the  heart,  vaso-motor  tonus  and 
pupil  mechanism,  are  extremely  often  disturbed  by  the 
action  of  poisons.  Many  poisons  act  on  all  these  func- 
tions simultaneously,  therefore  associating  them  in  some- 
what the  same  functional  analogy  in  so  far  as  they  are 
all  brought  into  a  condition  of  excitation  by  the  venosity 
of  the  blood  in  dyspnoea.  Poisons  may  either  exagger- 
ate or  annul  these  functions,  or  modify  the  frequency  of 
the  rhythmical  movements  under  their  control.  Very  often 
two  stages  occur  in  poisoning  by  one  drug,  first  an  in- 
creased vigor  of  function  and  acceleration  of  rhythm, 
then  enfeeblement  and  retardation.  The  characters  and 
methods  of  studying  these  changes  have  been  already 
given. 

With  these  alterations  of  functions  are  intimately  as- 
sociated the  motor  phenomena  of  irritation  produced 
directly  by  the  action  of  the  poison,  since  in  the  present 
status  of  physiology,  the  so-called  automatic  central 
stimulations  are  regarded  as  conditions  in  which  an  irri- 
tant acts  directly  on  the  nerve  centre,  and  not  the  con- 
duction of  an  irritant  through  the  centripetal  nervous 
system.  As  examples  of  this  form  of  toxic  stimulation 
may  be  mentioned  vomiting,  when  not  produced  by  toxic 
action  on  the  peripheral  nerve  endings,  intestinal  and 
uterine  contractions  from  action  on  the  brain  and  cord, 
and  general  convulsions  from  action  on  the  so-called 
'^  convulsive"  centre  in  the  medulla  ;  certain  of  these 
conditions  may  be  produced  by  a  high  degree  of  veno- 
sity of  the  blood,  a  fact  which  should  be  remembered  in 
forming  an  opinion  as  to  the  cause  of  the  phenomena. 

2.  Reflex  and  Co-ordinated  Functions. — In  the 
normal  state,  the  centripetal  impressions  produce  orderly 
reflexes,  which  are  capable  of  being  controlled  or  pre- 
vented by  automatic   inhibitory  centres  in  the  brain  or 


178  GENERAL    ACTION    OF    POISONS. 

by  the  will.  Poisons  can  modify  these  phenomena  in  the 
following  different  ways :  a.  The  limitation  of  the  re- 
flexes to  certain  single  normally  associated  motor  appa- 
ratus can  be  so  suspended  that  every  centripetal  impres- 
sion throws  the  entire  mass  of  centrifugal  fibres  into  ex- 
citement, thus  producing  general  convulsions  ;  these  re- 
flex convulsions  are  ordinarily  tetanic  in  character,  and 
each  part  of  the  body  assumes  the  condition  which  must 
follow  from  the  simultaneous  contraction  of  all  the  mus- 
cles associated  with  it.  Hence,  in  such  states  the  back 
is  hollowed  (opisthotonos),  the  head  extended,  the  jaws 
tightly  closed  (trismus),  and  the  limbs  extended.  In 
weaker  degrees  of  such  action,  as  well  as  in  initial 
stages  of  violent  action,  the  reflexes  are  only  abnormally 
increased  in  strength  and  in  the  number  of  associated 
muscles,  so  that  the  character  of  co-ordinated  movements 
is  lost.  These  convulsions  differ  from  those  described  in 
the  preceding  chapter,  in  that  they  can  only  be  inaugu- 
rated by  centripetal  impressions,  for  which,  however,  the 
lightest  toucher  jar  will  often  suffice. 

The  removal  of  all  forms  of  external  stimuli  can  only 
be  accomplished,  with  any  degree  of  certainty,  in  the 
case  of  frogs,  by  placing  them  under  a  bell-jar  on  some 
immovable  support. 

h.  On  the  other  hand,  poisons  can  weaken  or  entirely 
prevent  the  production  of  reflexes,  when  the  animals  lie 
absolutely  insensible  to  all  forms  of  stimulation :  ordi- 
narily this  condition  follows  the  state  of  attairs  described 
under  a. 

c.  The  reflex  inhibitory  apparatus  can  be  brought  into 
either  a  condition  of  increased  or  diminished  functional 
activity.     This  will  be  considered  directly. 

[In  order  to  study  the  action  of  drugs  on  the  reflex 
functions,  the  method  of  Tiirck  is  probably  the  best :  its 
principle  consists  in  comparative  measurements  of  the 
time  required  before  and  after  poisoning  for  a  given 
stimulus  applied  to  the  skin  to  evoke  a  reflex  muscular 
contraction  in  a  frog  from  whom  the  cerebral  hemi- 
spheres have  been  removed. 


ACTION    ON    THE    NERVOUS    SYSTEM.  179 

In  order  to  determine  the  state  of  the  reflex  functions  of 
the  spinal  cord,  the  brain  and  medulla  are  separated  from 
the  cord  by  an  incision  made  through  the  occipito-atlantal 
membrane :  this  locality  may  be  readily  recognized  by  the 
touch  as  a  depression  lying  in  the  median  line  of  the 
back  on  a  line  drawn  across  the  skull  at  a  tangent  to  the 
posterior  borders  of  the  membrana  tympani.  To  divide 
the  cord,  the  frog  is  held  in  the  left  hand,  and  the  head 
strongly  flexed  on  the  neck  by  the  left  thumb  ;  an  inci- 
sion, a  few  millimetres  in  length,  is  then  made  with  a 
sharp-pointed  knife  through  the  skin  and  membrane, 
care  being  taken  not  to  extend  it  too  far  to  the  sides, 
when,  on  removing  the  blood  with  a  sponge,  the  medulla 
will  come  into  view,  if  the  head  is  kept  well  flexed,  and 
may  be  divided.  This  method  is  preferable  to  one  thrust 
of  the  knife,  or  to  the  division  of  the  cord  with  the 
scissors,  when  it  can  never  be  known  whether  the  section 
is  complete  or  not.  The  brain  is  then  to  be  destroyed 
by  breaking  up  the  contents  of  the  skull  with  a  needle. 
The  hemorrhage  will  usually  soon  cease  :  should  it  con- 
tinue, it  may  be  checked  by  the  insertion  of  a  small  plug 
of  wood  into  the  opening  in  the  skull.  After  the  oper- 
ation, the  frog  should  be  placed  under  a  moist  bell-jar 
for  about  an  hour,  until  the  shock  of  the  operation  has 
passed  ofi".  At  first  the  limbs  will  all  be  extended,  and 
probably  no  motion  can  be  produced  by  irritation,  but 
after  a  while  the  limbs  will  be  drawn  up  and  a  more 
nearly  normal  attitude  be  regained,  marking  the  returning 
tone  of  the  spinal  ganglia. 

When  it  is  believed  that  the  shock  has  entirely  passed 
off,  the  frog  can  be  suspended  by  a  tack  or  hook  passed 
through  its  nose  to  some  suitable  support,  care  being 
taken  that  no  part  of  the  frog's  body  comes  in  contact 
with  any  solid.  Draughts  of  air  must  be  avoided,  and 
the  skin  must  be  prevented  from  drying  by  frequent  im- 
mersions in  a  basin  of  water.  A  test  liquid  is  then  made 
by  diluting  with  water  1  c.  c.  of  sulphuric  acid  to  a  litre  ; 
a  few  cubic  centimetres  of  this  acid  are  then  placed  in  a 
small  glass  beaker,  and  the  glass  brought  under  the  frog 


180  GENERAL    ACTION    OF    POISONS. 

and  elevated  until  the  tip  of  the  longest  toe  just  dips 
below  the  surface  of  the  acid,  and  the  length  of  time 
which  is  required  before  the  frog  withdraws  his  foot  de- 
termined by  counting  the  beats  of  a  metronome.  The 
instant  the  reflex  movement  occurs  the  entire  foot  must 
be  washed  in  a  large  beaker  of  water  to  remove  the  ex- 
cess of  acid  and  prevent  corrosion  of  the  skin  of  the  foot. 
The  time  elapsing  between  the  immersion  and  withdrawal 
of  the  foot  is  then  to  be  written  down,  and  after  waiting 
five  minutes,  the  experiment  repeated,  care  being  taken 
to  immerse  the  same  toe  to  precisely  the  same  extent  in 
each  trial.  These  experiments  are  to  be  repeated  until 
three  successive  trials  give  about  the  same  numbers, 
when  the  drug  can  be  injected  and  the  time  of  reflex  ac- 
tion compared  with  the  normal  standard.  It  is  probable 
that  most  substances,  which  are  at  all  irritating,  will  at 
first,  from  stimulation  of  the  sensory  nerves,  reduce  the 
spinal  reflex  irritability,  or,  in  other  words,  lengthen  the 
time  of  immersion. 

Every  reflex  action  requires  the  functional  activity  of 
a  sensory  nerve,  nerve  centre,  and  motor  nerve  ;  conse- 
quently, before  the  activity  of  the  spinal  ganglia  can  be 
studied,  the  sensory  and  motor  nerves  must  be  known  to 
preserve  their  functions  ;  therefore,  studies  of  the  action 
of  the  drug  on  the  peripheral  nervous  system  and  mus- 
cles, should  precede  the  examination  of  the  condition  of 
the  spinal  cord.  Should,  however,  for  any  reason,  this 
not  have  been  done,  and  it  be  found  that  after  the  admin- 
istration of  the  drug,  reflex  action  gradually  disappears, 
the  condition  of  the  motor  nerves  must  be  tested  with  a 
weak  induction  current ;  if  they  preserve  their  irritabil- 
ity, it  may  be  concluded  that  either  the  sensory  nerves 
or  spinal  centres  are  paralyzed.  The  latter  possibility 
may  be  excluded  by  first  ligating  the  bloodvessels  of  the 
limb  which  it  is  proposed  to  stimulate,  thus  protecting 
the  terminations  of  the  sensory  nerves  from  the  poison  ; 
if  the  reflex  irritability  is  now  depressed,  it  may  safely 
be  attributed  to  action  on  the  nerve  centres. 

The  same  method  may  be  employed  in  studying  reflex 


ACTION    ON    THE    NERVOUS    SYSTEM.  181 

action  in  the  case  of  drugs  which  are  known  to  paralyze 
the  sensory  nerves  ;  while  in  the  case  of  drugs  which 
paralyze  motor  nerves  or  muscles,  the  limb  opposite  to 
the  one  stimulated  may  be  protected  by  ligation. 

Having  determined  the  action  of  the  drug  on  the  spinal 
cord,  the  question  will  now  arise  as  to  its  action  on  the 
cerebral  inhibitory  centres  of  reflex  movement.  It  has 
been  discovered  by  Setschenow  that  the  optic  lobes  in  the 
frog  contain  centres,  stimulation  of  which  depresses  the  re- 
flex activity  of  the  spinal  cord,  while  their  removal  exalts 
it ;  though  no  doubt  can  exist  as  to  the  accuracy  of  these 
facts,  considerable  controversy  still  exists  as  to  their  ex- 
planation, but  until  more  conclusive  proof  is  brought  for- 
ward as  to  the  falsity  of  Setschenow's  theory,  we  will  ac- 
cept with  him  the  doctrine  of  special  spinal  inhibitory 
centres  in  the  optic  lobes,  whose  activity  is  capable  of 
being  stimulated  or  depressed  by  various  agents.  In 
order  to  study  the  action  of  drugs  on  these  centres,  all 
portions  of  the  cerebrum,  anterior  to  the  optic  lobes, 
must  be  removed  by  section  with  scissors  through  the 
skull,  on  a  line  with  the  anterior  margins  of  the  tympanic 
membranes.  After  observing  the  precautions  mentioned 
above,  the  normal  degree  of  reflex  irritability  is  deter- 
mined and  the  drug  administered;  should  the  activity  be 
depressed,  the  medulla  is  then  divided  on  a  line  with  the 
posterior  margins  of  the  tympanic  membranes,  and  the 
reflex  activity  again  tested.  If  it  is  then  found  that  the 
reflex  functions  are  greatly  exalted,  it  may  be  concluded 
that  the  initial  depression  was  due  to  stimulation  of 
Setschenow's  centres.  Or,  on  the  other  hand,  drugs 
may  paralyze  these  inhibitory  centres  and  so  bring  the 
reflex  activity  of  the  cord,  even  w^hen  in  connection  with 
the  medulla,  up  to  the  normal  degree  of  the  isolated  cord. 
In  the  removal  of  the  cerebrum,  care  must  be  taken  to 
avoid  hemorrhage,  which  is  a  stimulant  to  Setschenow's 
centre,  as  is  also  a  decreased  action  of  the  heart.  It  has 
also  been  urged  by  W.  T.  Sedgwick,^  that  the  depression 

'  Journ.  of  PhvsioL,  vol.  iii.  No.  1. 
16 


182  GENERAL    ACTION    OF    POISONS. 

of  reflex  action  following  the  administration  of  quinine  is 
due  to  stimulation  of  the  afferent  fibres  of  the  vagus 
nerve,  an  inhibitory  effect  on  the  spinal  centres  being 
produced  in  the  same  way  as  when  any  afferent  nerve  is 
stimulated.] 

In  addition  to  these  general  disturbances  of  reflex 
action,  poisons  can  also  influence  individual  reflexes ;  but 
since  these  reflex  centres  are,  in  all  probability,  identical 
Avith  the  co-ordinating  centres,  it  cannot  ordinarily,  as  in 
spasm  of  the  muscles  of  deglutition,  be  determined  whether 
the  toxic  action  is  exerted  directly  on  the  centres  of  co- 
ordination, or  whether  their  reflex  stimuli  are  only  abnor- 
mally increased.  The  position  is  here  much  the  same  as 
in  the  case  of  general  reflex  convulsions  (strychnia 
tetanus),  where  the  question  whether  the  spasms  are 
evoked  by  external  stimuli  can  only  be  settled  on  the 
frog,  and  not  on  the  warm-blooded  animals. 

3.  Action  on  the  Sensory  Functions. — As  already 
stated,  toxic  disturbances  of  the  sensory  functions  can  be 
studied  with  any  degree  of  certainty  only  on  man.  The 
class  of  drugs  which  can  be  thus  examined  is  consequently 
extremely  limited,  adding  still  another  difficulty  to  an 
already  obscure  subject. 

These  toxic  sensory  phenomena  consist  of  two  consecu- 
tive stages:  1.  The  stage  of  excitation,  with  its  conse- 
quent phenomena,  a.  The  sensory  perceptions  no  longer 
preserve  their  normal  relation  to  the  objective  stimulant, 
but  exist  in  relatively  increased  intensity,  thus  producing 
an  increased  sensibility  ;  errors  in  the  estimation  of  the 
character  of  the  stimuli  may  also  be  produced,  and  in 
marked  toxic  conditions  sensory  peceptions  (subjective) 
may  be  produced  without  apparent  cause. 

b.  In  slight  degrees  of  this  form  of  toxic  action  the 
flow  of  ideas  is  facilitated  and  the  mental  processes  stimu- 
lated, though  mental  control  is  diminished ;  in  severe 
forms  of  intoxication  the  mental  processes  are  entirely 
uncontrollable  and  disorderly,  giving  rise  to  the  various 
forms  of  toxic  mania  and  hallucinations. 

c.  In   slight  degrees  of  poisoning  the  normal  control 


ACTION    ON    THE    NERVOUS    SYSTEM.  183 

of  the  voluntary  movements  is  lost,  the  muscles,  perhaps 
from  disturbance  of  the  muscular  sense,  contracting 
more  or  less  powerfully  than  was  intended,  thereby  pro- 
ducing various  disturbances  in  locomotion  or  speech,  while 
in  severe  forms  of  intoxication  the  power  of  performing 
normal  movements  is  entirely  lost,  and  complete  paralysis 
or  general  or  localized  convulsions  result.  The  cerebral 
stimuli  of  movement  may  also  be  disturbed  and  lead  to 
various  maniacal  acts  ;  the  highest  forms  of  these  sensory 
disturbances  constitute  delirium. 

2,  The  stage  of  depression  is  characterized  by  phe- 
nomena opposed  in  every  respect  to  those  just  mentioned; 
in  moderate  degrees  of  intoxication,  sluggish  senses,  ob- 
tuse mental  acts,  and  indisposition  to  move;  in  higher 
degrees,  complete  loss  of  consciousness  (sleep),  and  de- 
pression of  all  the  reflexes,  with  impossibility  of  being 
aroused  (soper,  coma,  narcosis).  In  the  case  of  many 
poisons  these  last-named  phenomena  may  precede  the 
above  mentioned,  or  exist  alone  as  special  actions  of  the 
drug. 

Another  sensory  disturbance,  less  often  produced  by 
drugs  than  by  other  causes,  is  syncope  ;  it  consists  of  loss 
of  consciousness  without  the  symptoms  described  above 
as  constituting  the  initial  stage  of  excitement. 

The  only  premonitory  symptoms  of  syncope  are  found 
in  disturbances  of  special  senses  (darkness  before  the 
eyes)  and  disturbance  of  muscular  co-ordination  (dizzi- 
ness, staggering),  appearing  before  complete  loss  of  con- 
sciousness is  established. 

The  toxic  sensory  disturbances  may  depend  either  upon 
direct  action  on  the  cerebrum  or  upon  disturbances  of 
respiration  or  circulation,  both  of  which  are,  however* 
functions  essentially  under  the  control  of  the  central 
nervous  system.  Disturbance  of  respiration  may  merely 
produce  loss  of  consciousness,  and  that  only  in  the  stage 
of  asphyxia  through  insufficient  supply  of  oxygen  ;  while 
circulatory  disorders  may  produce  the  most  manifold 
sensory  symptoms  as  soon  as  the  blood-pressure  in  the 
cerebral  vessels  suflfers  any  considerable  change  ;  thus 


184  GENERAL    ACTION    OF    POISONS. 

syncope  may  be  caused  by  depression  of  the  blood-pres- 
sure from  diminished  vigor  of  cardiac  contraction.  The 
effects  of  increased  arterial  pressure  and  of  venous  stag- 
nation are  less  clear ;  both  conditions,  of  which  the  first 
alone  can  be  regarded  as  a  direct  toxic  result  (from  pa- 
ralysis of  the  cerebral  bloodvessels,  increased  force  of  the 
heart's  action,  or  contraction  of  the  peripheral  vessels),  are 
usually  designated  as  congestion  of  the  brain,  and  since 
post-mortem  examinations  in  cases  of  poisoning  accompa- 
nied by  sensory  phenomena  often  reveal  positive  changes, 
such  as  hyperaemia  of  the  brain  and  its  membranes,  the 
anatomical  conditions  are  supposed  to  be  a  cause  of  the 
symptoms.  This  hypersemic  condition  of  the  brain  is 
often  manifested  during  the  action  of  the  poison  by  con- 
gestion of  the  face,  injection  of  the  eyes  and  increased 
secretion  of  tears  and  saliva  ;  while  in  many  cases  even 
actual  rupture  of  the  vessels  (cerebral  apoplexy)  may 
be  produced. 

Though  it  is  acknowledged,  as  is  proved  by  the  symp- 
toms occurring  in  cerebritis  or  meningitis,  that  hyperemia 
of  the  brain  may  cause  symptoms  similar  to  those  de- 
scribed above,  there  is  no  means  of  proving  absolutely, 
that,  in  the  production  of  these  symptoms  by  poisons,  the 
same  processes  are  concerned;  accordingly,  unless  the 
contrary  can  be  proved,  it  is  not  unwarrantable  to  as- 
cribe the  sensory  toxic  effects  of  drugs  to  direct  action 
on  the  cerebral  centres. 

The  proof  of  circulatory  disturbance  in  the  brain  is 
only  obtained  with  the  greatest  difficulty.  The  post- 
mortem appearances  are  apt  to  be  deceptive,  since  it  is 
conceivable  that  transient  circulatory  changes  may  exist 
without  leaving  any  characteristic  post-mortem  appear- 
ances, and  congestion  etc.  (except,  of  course,  active  in- 
flammation), may  be  produced  during  the  death  struggle. 
During  life,  observation  of  the  retinal  vessels  with  the 
ophthalmoscope  will  give  a  tolerably  accurate  idea  as  to 
the  state  of  the  cerebral  circulation.  Direct  inspection 
in  animals  is  rendered  possible  by  trephining,  a  glass 
plate  being  inserted,  after  the  method  of  Donders,  in  the 


EXPLANATION   OF  ANATOMICAL  ALTERATIONS.      185 

opening  in  the  skull;*  by  this  means,  however,  only  the 
surface  is  exposed  to  inspection.  As  regards  the  general 
condition  of  the  cerebral  circulation,  some  idea  may  be 
obtained  by  manometric  examination  of  the  pressure 
within  the  skull,  but  this  procedure,  as  far  as  is  known, 
has  never  been  applied  to  pharmacological  studies.^ 


INVESTIGATION  AND  EXPLANATION  OF  THE  ANATOMICAL 
ALTERATIONS  PRODUCED  BY  POISONS. 

The  anatomical  changes  produced  by  the  action  of  poi- 
sons can  be  studied  only  in  the  most  limited  degree  during 
life,  as  in  inflammation  at  the  point  of  absorption,  when 
visible  to  the  eye,  or  increase  or  decrease  of  fatty  tissue, 
etc.  Most  anatomical  changes  can  only  be  recognized 
after  death,  and  it  is,  therefore,  advisable,  in  order  to 
obtain  a  complete  picture  of  the  morbid  processes,  to  kill 
the  animals  experimented  on  in  different  stages  of  the 
poisoning. 

No  general  rules  can  be  given  for  the  investigation  of 
these  points,  since  they  will  depend  upon  the  nature  of  the 
pathological  process.  An  attempt,  however,  should  in- 
variably be  made  to  determine  whetlier  the  changes  are 
due  to  direct  action  on  the  tissue  concerned,  or  whether 
they  are  secondary  results  from  some  functional  distur- 
bance. In  general,  the  latter  state  of  affairs  will  be 
found  to  exist,  except  of  course  in  cases  in  which  the 
results  are  evidently  attributable  to  inflammation  of  the 
absorbing  surface. 

'  The  procedure  is  described  by  Krause,  in  Anat.  des  Kaiiin- 
cheiis,  p.  46. 

*  Various  methods  of  investigation  of  the  cerebral  circulation  are 
given  in  the  Medical  Lancet,  Oct.  1850,  Moleschott's  Untersuch., 
iii.,  Virchow's  Archiv,  xxxvii.  519,  and  Monographs  by  Jolly, 
Wurzburg,  1871,  Althann,  Dorpat,  1871,  Pagenstecher,  Heidelberg, 

16* 


186  GENERAL    ACTION    OF    POISONS. 

A  large  number  of  poisons,  among  which  are  the 
nerve  poisons  -which  probably  produce  some  obscure 
chemical  change  in  the  nerve  elements,  leave  no  detecta- 
ble post-mortem  trace  of  their  action,  thus  proving  that  the 
most  profound  functional  disturbance  may  exist  without 
any  palpable  tissue  change. 

In  the  examination  of  post-mortem  appearances,  ac- 
count must  be  taken  of  the  changes  which  can  be  attri- 
buted to  the  act  of  dying,  and  it  is  not  sufficient  merely 
to  separate  the  normal  post-mortem  processes  of  coagu- 
lation in  blood  and  muscle  and  the  changes  of  decompo- 
sition, from  the  effects  due  to  the  action  of  the  drug.  In 
most  forms  of  death,  a  large  number  of  changes,  in  no 
way  characteristic  of  the  special  cause  of  death,  are 
produced  by  the  stoppage  of  circulation  and  respira- 
tion. Among  these,  the  ordinary  asphyxic  appear- 
ances are  the  most  usual,  since  nearly  every  form  of 
death  occurs  under  the  symptoms  of  suffocation.  It  is 
further  to  be  noted  that  the  characteristic  changes  pro- 
duced by  the  poison,  where  such  exist,  may  be  modified 
or  removed  during  the  act  of  dying.  Moreover,  no  re- 
liable conception  can  be  obtained  as  to  the  state  of  the 
cerebral  circulation,  or  the  amount  of  fluid  in  the  brain, 
from  the  post-mortem  changes,  since  such  conditions  are 
sure  to  be  disturbed  in  the  death  struggle,  and  the  un- 
certainty will  be  the  greater  the  longer  the  act  of  dying 
is  prolonged.  When,  therefore,  it  is  desired  to  examine 
into  these  points,  the  animal  should  be  killed  by  punc- 
ture of  the  medulla,  so  as  to  prevent  the  signs  of  dys- 
pnoea or  convulsions  being  confounded  with  those  directly 
due  to  the  poison. 

Alterations  due  directly  to  the  action  of  the  poison 
can,  with  any  degree  of  certainty,  be  only  detected  at 
the  point  of  absorption  of  the  poison  ;  particularly  when 
the  poison  is  of  a  diffusive  character,  and  so  apt  to  pene- 
trate deeply  into  the  tissues  without  following  the  vessels. 
Such  chaniies  are  usually  of  a  corrosive  character  ;  that 
is,  chemical  destruction  of  the  tissue  elements,  with  its 
consequent  inflammatory  changes. 


EXPLANATION   OF   ANATOMICAL  ALTERATIONS.     187 

[Degenerative  changes  and  changes  in  the  histological 
elements  at  the  point  of  application  will  also  fall  under 
the  heading  of  local  action.  Thus  Erdss  found  that  in- 
jections of  oil  of  mustard  into  muscles  caused  fatty  de- 
generation and  disappearance  of  their  transverse  striae.] 

These  alterations  must,  from  their  very  nature,  be 
restricted  to  the  points  with  which  the  poison  comes  in 
direct  contact,  since  after  absorption  by  the  bloodvessels 
the  poison  either  undergoes  chemical  change,  or  is  so 
diluted  as  to  be  unable  to  produce  its  corrosive  effects. 
The  action  of  poisons  administered  by  the  alimentary 
canal  may,  of  course,  be  spread  over  a  very  extended 
surface.  Usually,  however,  the  corrosive  action  of  a 
poison  is  restricted  to  the  point  of  application,  and  to  the 
depth  to  which,  in  a  concentrated  form,  it  is  capable  of 
diffusing. 

When  the  absorbing  surface  has  thin  walls,  as  is  the 
case  in  the  stomach  or  intestines,  the  irritant  action  may 
extend  through  diffusion,  by  continuity  of  surface,  to 
neighboring  organs,  such  as  the  liver,  spleen,  or  dia- 
phragm. If  the  action  leads  to  perforation,  the  poison 
may  gain  access  to  the  body  cavities,  and  thus  come  in 
contact  with  greatly  increased  surfaces. 

In  addition  to  this  irritant  action  and  its  sequellae 
(such  as  hypersemia,  catarrh,  swelling,  suppuration,  in- 
filtration, degeneration,  and  scarring),  but  few  specific 
toxic  anatomical  changes  can  be  detected.  When  such  ex- 
ist, they  are  generally  to  be  found  in  the  glands  and  mus- 
cles (fatty  degeneration),  and  skin  (exanthemata),  and 
are  only  produced  when  the  action  of  the  poison  has  not 
been  rapidly  fatal.  The  connecting  links  between  the  di- 
rect action  of  the  poison  and  these  secondary  results  are 
hidden  in  the  greatest  obscurity.  It  can  only  be  said 
that  they  are  due  to  changes  in  nutrition  without  any 
explanation  being  possible.  In  many  cases  the  locality 
of  these  changes  appears  to  depend  upon  the  course  of 
the  poison  in  the  system  ;  thus  kidney  changes  may  be 
produced  by  drugs  eliminated  through  the  urine,  so, 
perhaps,  showing  that  they  are  due  to  direct  anatomical 
action  of  the  poison. 


188  GENERAL    ACTION    OF    POISONS, 


VI. 

INVESTIGATION  OF  CHEMICAL  CHANGES  PRODUCED  BY 
POISONS. 

Of  the  chemical  processes  resulting  from  the  adminis- 
tration of  drugs  (see  page  80),  only  those  will  be  here 
alluded  to  which  may  serve  to  add  to  our  knowledge 
of  the  mode  of  action  of  the  drug.  Changes  in  the 
composition  of  the  poison  will  not  here  come  under 
consideration.  These  investigations,  so  far  as  they  do 
not  concern  alteration  of  the  secretions,  can  only  be 
undertaken  post  mortem,  and  here,  even  more  than  in 
the  study  of  anatomical  alterations,  great  care  must  be 
taken  in  excluding  the  results  of  post-mortem  changes ; 
consequently,  the  examinations  should  be  made  immedi- 
ately after  death.  Since  the  normal  chemical  constitu- 
ents of  different  organs  are  but  imperfectly  known, 
and  the  actions  of  poisons  probably  involve  obscure 
chemical  changes,  but  little  can  be  here  said  ;  especially 
as  the  constituents,  of  which  our  knowledge  is  at  all  com- 
plete, are  either  products  of  tissue  change,  already  des- 
tined for  elimination,  or  decomposition  products  of  the 
unstable  tissue  elements,  produced  in  post-mortem  changes 
or  in  the  chemical  manipulations  required  in  the  analysis. 

In  the  case  of  nerve  and  muscle  poisons  it  cannot  be 
stated  whether  their  action  is  due  to  chemical  change 
or  not.  In  the  case  of  the  direct  action  of  poisons  on  the 
blood,  as  far  as  combinations  with  the  gases  of  the  blood 
are  concerned,  our  information  is  more  definite. 

The  study  of  toxic  disturbances  of  nutrition  often  pro- 
duced by  poisons,  with  the  exception  of  estimation  of 
sugar  and  glycogen,  when  post-mortem  changes  should  be 
prevented  by  boiling  water,  are  probably  better  carried  on 
indirectly  through  examination  of  the  excretions,  rather 
than  in  direct  analysis  of  the  different  organs. 

The  greatest  number  of  investigations  as  to  the  post- 
mortem presence  of  poisons  in  the  body  have  been  un- 
dertaken for  medico-legal  purposes,  a  class  of  study  which 
does  not  fall  within  the  province  of  this  work. 


APPENDIX 


1.  Doses,  Immunities,  Form,  and  Solvents  of  Pox 
SONS. — To  obtain  a  complete  idea  as  to  the  action  of  a 
poison,  it  must  be  administered  in  doses  varying  from 
the  smallest  active  quantity  to  maximum  doses ;  that  is, 
until  a  point  has  been  reached  when  increase  in  the  dose 
causes  no  increase  in  the  character  or  intensity  of  the 
resulting  symptoms.  This  is  not  only  necessary  on  prac- 
tical grounds  (since  to  be  of  therapeutic  value,  it  must  be 
known  what  quantities  are  fatal  and  what  is  the  smallest 
amount  that  will  produce  any  effect),  but  more  especially 
because  very  often  the  effects  of  a  poison  will  be  found 
to  vary  with  the  quantity  used.  This  graduation  of  dose 
must  be  established  for  each  class  of  animal  experimented 
on,  since  it  will  often  be  found4hat  corresponding  doses 
will  produce  different  results  in  different  classes  of  ani- 
mals. Many  poisons  are  entirely  inert  on  certain  species, 
while  very  virulent  on  others ;  but  occasionally  it  will 
be  found  that  this  immunity  is  only  apparent,  the  result 
being  due  merely  to  a  difference  in  the  dose  required. 
When  such  immunities  are  detected  it  is  an  interesting 
question  to  attempt  to  explain  their  cause.  Before  all, 
an  apparent  immunity  must  be  separated  from  one  which 
is  actual ;  apparent  immunities  exist  when,  although  the 
fundamental  action  of  the  poison  is  exerted,  it  causes  only 
such  functional  disturbances  as  do  not  produce  any  evident 
effect  on  the  organism  ;  such  as  the  apparent  immunity 
of  frogs  to  carbonic  oxide.  In  actual  immunities  the  ac- 
tion of  the  poison  is  not  exerted,  or  only  after  the  admin- 
istration of  disproportionately  large  doses.    The  cause  of 


190  APPENDIX. 

such  immunities  cannot  be  positively  stated,  though  the 
following  may  be  urged  as  possible  explanations  :  «,  the 
chemical  conditions  necessary  for  the  action  of  the  poison 
do  not  exist  in  the  animal  experimented  on;  an  example 
of  this  is  seen  in  the  immunity  enjoyed  by  insects  for 
carbonic  acid,  since  their  respiration  is  not  carried  on 
with  haemoglobin ;  6,  the  nutritive  changes  occurring  in 
the  animal  may  be  of  such  a  character  as  to  cause  such 
an  unusually  rapid  excretion  or  decomposition  of  the  poi- 
son as  not  to  allow  the  accumulation  in  the  blood  of  a 
quantity  sufficient  to  produce  toxic  action.  Such  a  pro- 
cess- may  be  established  when  the  prevention  of  excretion, 
as  by  ligation  of  the  ureters,  renders  a  much  smaller  dose 
active.  Actual  immunities  may  be  determined  by  the 
detection  of  the  poison  in  the  animal  tissues ;  thus,  the 
above  explanation  will  not  apply  to  the  immunity  of  rab- 
bits to  belladonna,  for  their  flesh,  after  they  themselves 
have  received  unharmed  large  quantities  of  belladonna, 
will  produce  symptoms  of  atropia  poisoning  when  con- 
sumed by  man  or  other  animals.  Under  no  circumstances 
can  any  explanation  be  attempted  unless  all  the  modes 
of  action  of  the  poison  are  thoroughly  understood.  With 
the  exception  of  cases  in  which  special  immunities  exist, 
the  general  law  holds  good  that  the  dose  required  to  pro- 
duce the  general  action  of  a  poison  is  in  accordance  with 
the  size  of  the  animal ;  this  is  readily  understood  when 
it  is  remembered  that  a  certain  percentage  of  poison  in 
the  blood  is  required  before  the  effects  of  the  poison  are 
manifested,  and  of  course  as  the  amount  of  blood  con- 
tained in  a  small  animal  is  less  than  that  of  a  larger  one, 
a  smaller  dose  is  required  to  produce  proportionate 
effects.     This  rule  has,  however,  many  exceptions. 

In  many  cases  it  is  necessary  to  repeat  the  doses  at 
intervals  in  order  to  prolong  the  period  of  poisoning, 
and  permit  extended  observation  of  any  particular 
stage  ;  often,  however,  this  will  be  impossible,  as  ani- 
mals will  frequently  lose  their  susceptibility  to  repeated 
doses  of  a  poison.  Such  reduced  susceptibility  occurs 
with  nicotin,  and,  indeed,  remains  after  the  cessation  of 


IMMUNITIES    TO    POISONS.  191 

the  administration  of  the  drug  ;  such  conditions  may  be 
described  as  acquired  immunities,  or  the  animal  or  per- 
son is  said  to  become  habituated  to  the  poison :  its  ex- 
planation is  one  of  the  most  difficult  problems  of  phar- 
macology. 

The  repeated  administration  of  drugs  is  further  neces- 
sary from  another  point  of  view,  since  many  poisons  only 
produce  certain  effects  after  repeated  administration : 
ordinarily  under  such  circumstances  the  organism  under- 
goes such  changes  that  a  single  dose  is  not  capable  of 
producing  the  characteristic  eifects  of  the  drug.  Thus 
a  number  of  poisons  require  prolonged  contact,  or  that 
of  their  products,  with  the  special  organs  on  which  they 
act ;  consequently  a  single  dose  is  not  capable,  on  ac- 
count of  rapid  elimination,  of  producing  its  typical  ac- 
tion. The  effect  cannot  even  be  produced  by  increasing 
the  dose  of  the  poison  ;  because,  on  the  one  hand,  it  may 
cause  death  by  some  other  mode  of  action,  or,  on  the 
other  hand,  there  is  a  limit  to  the  quantity  of  poison 
capable  of  absorption,  especially  in  the  more  insoluble 
poisons  in  which  the  amount  administered  is  of  little  con- 
sequence, as  the  excess  over  and  above  that  which  can 
be  absorbed  is  carried  off  by  the  feces,  when  given  by 
the  stomach,  or  by  suppuration  when  given  subcutane- 
ously.  In  such  cases  the  repeated  administration  of  the 
poison  is  indispensable  for  the  production  of  the  charac- 
teristic action. 

Such  cases  are  designated  by  the  expression  chronic 
poisoning,  an  unfortunate  term,  since  chronic  .poisoning 
is  not  separated  from  the  acute  form  by  the  time  re- 
quired for  its  development,  or  the  duration  of  its  exist- 
ence, but  by  the  fact  that  acute  poisoning  is  caused  by  a 
single  dose,  chronic  poisoning  by  doses  repeated  at  in- 
tervals. (1)  To  this  class  of  chronic  poisonings  belong 
the  cases  of  so-called  cumulative  action;  that  is,  effects 
which  only  appear  after  the  repeated  administration  of 
separate  doses,  even  though  they  be  small,  and  which 
cannot  be  caused  by  the  administration  of  a  single  dose, 


192  APPENDIX. 

even  though  it  be  a  large  one.      The  cause  can  only  lie 
in  the  explanation  given  above. 

Another  case  in  which  the  characteristic  action  may 
only  be  produced  by  repeated  small  doses  is  when  larger 
doses,  by  some  special  action,  such  as  vomiting,  or  defe- 
cation, either  prevent  absorption,  or  cause  such  rapid 
elimination,  that  either  no  action,  or  a  modified  one,  oc- 
curs. 

The  physical  form  in  which  the  poison  is  administered 
is  of  great  influence  on  its  mode  and  conditions  of  ac- 
tion. It  is  only  when  in  solution  that  a  poison  can  enter 
the  blood  by  absorption,  and  the  rapidity  of  absorption 
depends  largely  on  the  character  of  the  solvent;  and  upon 
the  rapidity  of  absorption  will  depend  the  character 
or  even  the  existence  of  the  general  action.  Poisons, 
introduced  in  the  solid  form,  often  find  solvents  in  the 
difi'erent  fluids  of  the  body,  especially  in  the  water  of  the 
tissue  juices  and  secretions,  which  will  permit  this  ab- 
sorption. These  natural  solvents  should  not,  however, 
be  relied  upon,  but  the  drug  be  invariably  administered 
in  solution,  since  the  abstraction  of  water  from  the  tis- 
sues may  set  up  inflammatory  changes  which  might  com- 
plicate the  result,  or  the  solvent  might  not  be  on  hand 
in  sufficient  quantity  to  dissolve  the  amount  of  drug 
administered  ;  thus,  for  example,  it  is  possible  that  in 
acute  phosphorus  poisoning,  the  phosphorus  is  ab- 
sorbed without  producing  local  inflammatory  changes 
when  fat  is  found  at  the  same  time  in  the  digestive 
canal. 

In  the  choice  of  a  solvent,  one  must  be  selected  that 
is  itself  absorbable  and  indifferent  (inactive),  and  the 
solution  should  not  be  too  concentrated,  as  concentrated 
solutions,  like  the  solid  body,  tend  to  produce  corrosive 
eff'ects. 

2.  Methods  of  Producing  Narcosis. — For  a  num- 
ber of  special  pharmacological  studies  it  is  necessary, 
before  giving  the  poison  under  study,  to  give  some  drug 
which  will  destroy  certain  functions  which  it  is  desired  to 


METHODS    OF    PRODUCING    NARCOSIS.  193 

eliminate.  Ordinarily  it  is  desired  to  maintain  the  ani- 
mal in  a  passive  condition,  in  which  no  voluntary  mo- 
tions will  be  made,  and  curare,  therefore,  is  the  drug 
most  frequently  used,  either  to  produce  absolute  motion- 
lessness  in  complicated  experiments,  as  in  blood- 
pressure  experiments,  or  to  eliminate,  through  paralysis 
of  the  motor  nerve  endings,  the  possible  effect  of  the 
drug  on  these  organs.  In  all  cases  of  curare  poisoning 
in  warm-blooded  animals,  artificial  respiration  must  be 
maintained.  Curare  must  not  be  used  in  the  study  of  • 
drugs  which,  a,  act  themselves  on  the  motor  apparatus, 
or,  6,  which  produce  diabetes,  since  the  latter  is  also 
caused  by  curare,  or,  c,  it  must  be  used  only  in  very 
small  doses  when  the  drug  under  study  itself  acts  on  the 
vaso-motor  nerves. 

Whenever  any  drug  is  used  for  these  purposes,  all  its 
actions  must  be  thoroughly  understood,  and  must  not  be 
incompatible  with  the  drug  under  study,  unless  the  line 
of  incompatibility  can  be  sharply  drawn,  and  may  itseli 
serve  such  purposes  as  above  alluded  to. 

Chloral  is  often  employed  to  destroy  pain  and  keep 
the  animal  motionless,  and  does  not  require  the  main- 
tenance of  artificial  respiration ;  it  is  especially  suited 
for  rabbits,  which,  as  a  rule,  do  not  stand  narcotics  well. 
Chloral,  however,  cannot  be  used  in  the  study  of  the 
action  of  poisons  on  the  heart,  vessels,  or  pupil. 

Morphia,  or  laudanum,  may  be  used  for  the  same  pur- 
poses, and  with  the  same  limitations  ;  both  are  well  suited 
for  dogs. 

These  drugs  are  not,  however,  as  yet  thoroughly 
enough  understood  to  allow  of  certainty  that  they  exert  no 
antagonism  on  the  action  of  the  special  poison  which  may 
be  the  subject  of  study  ;  they  should  therefore  only  be 
used  in  special  cases,  and  control  experiments  should 
always  be  made  without  the  use  of  any  narcotic  in  order 
to  determine  the  general  action  of  any  drug. 

17 


194  APPENDIX 


Antagonism  of  Drugs. 

[No  study  of  the  action  of  a  drug  can  be  considered 
complete  unless  some  attempt  has  been  made  to  discover 
its  physiological  antidote.  The  chemical  antidotes  of  a 
drug,  when  such  exist,  are  usually  readily  determined 
by  its  known  chemical  incompatibilities.  The  practical 
value  of  such  knowledge  is,  however,  restricted  in  cases 
of  actual  poisoning  to  the  time  during  which  the  poison 
remains  within  the  alimentary  canal ;  thus  alkalies  can 
only  be  useful  immediately  after  the  ingestion  of  acids  ; 
iron  hydrated  sesquioxide,  immediately  after  the  admin- 
istration of  arsenic.  By  physiological  antagonism,  how- 
ever, as  expressed  by  Bartholow,^  is  meant  a  balance  of 
opposed  actions  on  particular  organs  or  tissues.  This 
antagonism,  or  opposition  of  actions,  may  extend  through- 
out the  whole  range  of  effects  of  two  diiferent  drugs,  or 
it  may  be  limited  to  a  few  points  ;  and,  indeed,  some  of 
the  most  valuable  instances  of  antagonism  are  thus 
limited,  and  there  are  few,  if  any,  examples  in  which 
the  opposition  of  actions  is  universal.  In  the  search, 
therefore,  for  a  physiological  antagonist,  a  drug  should 
be  first  selected  in  which  the  points  of  contrast  in  physi- 
ological action  are  most  marked.  Thus,  when  it  has 
been  determined  that  the  poison  under  study  destroys 
life  by  paralysis  of  the  respiratory  centre,  a  marked 
stimulant  of  that  centre  should  first  be  tested  as  to  its 
possession  of  antidotal  powers.  A  cardiac  depressant 
should  be  antagonized  with  a  cardiac  stimulant,  etc. 

When  a  drug  has  been  selected  which  offers  the 
greatest  number,  or  most  pronounced,  points  of  contrast 
to  the  poison  under  study,  the  first  point,  if  not  already 
settled,  will  be  to  determine  the  minimum  fatal  dose  of 
the  poison  per  pound  weight  of  the  animals  experimented 
on ;  then  the  minimum  fatal  dose  of  the  drug  wliich  it 
is  proposed  to  test  as  an  antidote.     This  having  been 

'  Antagonism  between  Medicines,  Cartwriglit  Lectures,  1880. 


ANTAGONISM    OF    DRUGS.  195 

accomplished,  the  minimum  lethal  dose  of  the  poison  is 
administered,  to  be  followed  by  the  administration  within 
a  few  minutes  of  the  corresponding  dose  of  the  antidote. 
Should  the  animal  survive,  the  same  dose  of  the  poison 
should  then  be  administered  a  few  days  later  to  test 
whether  the  dose  originally  given  was  sufficiently  large  to 
cause  death.  After  a  drug  which  possesses  antidotal  pro- 
perties has  been  found,  and  the  proper  dose  determined, 
the  antidote  and  the  poison  may  be  given  simultaneously. 
Experiments  should  also  be  made  as  to  the  time  which 
may  elapse  and  the  poisoned  animal  still  be  saved  by 
the  antidote,  and  as  to  how  much  more  than  the  minimum 
fatal  dose  of  the  poison  may  be  given  and  the  animal's  life 
still  be  preserved  by  the  antidote.  A  curious  fact  which 
has  been  over  and  over  again  demonstrated,  and  should 
be  remembered  in  such  investigations,  is  that  when  less 
than  the  minimum  fatal  doses  of  two  poisons,  which 
modify  each  other's  action,  are  given  simultaneously, 
death  will  often  result. 

After  a  successful  antagonism  has  been  proved,  it  will 
then  be  interesting  to  see  in  what  manner  the  fatal  effects 
are  prevented.  To  that  end,  if  the  drug  is  a  circulatory 
poison,  for  instance,  paralyzing  the  vagi  and  vaso-motor 
centre,  a  blood-pressure  experiment  should  be  made,  and 
when  the  characteristic  effects  have  been  produced,  an 
appropriate  dose  of  the  antidote  should  be  given  and 
the  effects  on  the  circulation  noted ;  whether  the  blood- 
pressure  rises  and  the  vagi  and  vaso-motor  centre  regain 
their  irritability.  If  the  action  is  on  the  heart  or  respi- 
ratory centre,  experiments  such  as  those  already  detailed 
under  the  heading  of  the  circulation  or  respiration  may 
be  instituted.] 


INDEX. 


ABSORPTION  of  poisons,  64 
Accelerator  cardiac   ganglia, 
106 
action  of  poisons  on, 
124 
nerves,  108,  109 
Administration  of  poisons,  63 
Albuminoids  of  blood,  action  of 

poisons  on,  23 
Amoebae,  action  of  poisons  on,  59 
Anatomical  alterations  produced 

by  poisons,  185 
Animals,  modes  of  securing,  60 

selection  of,  55 
Antagonism  of  drugs,  194 

of  poisons  on  heart,  123 
Antidotes,  modes  of  detecting,  194 
Apnoea,  134 
Appendix,  189 

Arteries,  injections  into,  67,  68        | 
Artery,  carotid,  preparation  of,  67  j 
femoral,  ligation  of,  33,  67 
iliac,  ligation  of,  33 
Artificial  respiration  apparatus,  76 
Asphyxia,  production  of,  134 
Assimilation  of  poisons,  80 
Auricle,  action  of  poisons  on,  121 
Automatic  functions,  interference 
with,  177 


"DACILLI,  action  of  poisons  on. 

Bacteria,  action  of  poisons  on,  59 
Bile,  eflects  of  retention  of,  143 
Biliary  fistulse,  mode  of  making, 
151 
secretion,  action  of  drugs  on, 
150 
Blood,  action  of  poisons  on,  20 
alterations  in  coagulability  of, 
28  I 

in  coloring  matter  of,  29 
in  consistence  of,  23  ' 

17 


Blood,  alterations — 

in  ozone  of,  30 
in  reaction  of,  23 
cause  of  venosity  of,  133 
corpuscles,  alterations  in,  25, 

28 
gases,  alterations  in,  30 
modes  of  collecting,  22 

of  passing  gases  through, 
26 
pressure,  action  of  poisons  on, 
111 
determination  of,  102, 104 
experiments,  mode  of  con- 
ducting, 92,  98 
tracings,  103 
Bloodvessels,  action  of  poisons  on, 
125 
injections  into,  05 
ligation  of,  33 
modes  of  exa^iining,  125 
Brain,  changes  in  circulation  of, 
184 
influence  of  disturbed  circula- 
tion on, 130 
Bronchi,  injections  into,  72 


CANULiE,  arterial,  102 
methods  of  making,  20 
mode  of  inserting,  21 
Cardiac  ganglia,  106 
Cardiograph,  Sanderson's,  89 
Carotid  artery,  preparation  of,  67, 

99 
Cats,  mode  of  fastening,  61 
Cerebrum,  influence  of  circulation 

on, 130 
Changes  of  poisons  in  the  body,  77 
Chemical  changes  in  muscle,  48 
in  poisons,  80 
produced    by    poisons, 
187 
Chloral  as  a  narcotic,  193 


198 


INDEX. 


Chorda  tympani  nerve,  mode  of 

exposing,  149 
Chronic  poisoning,  191 
Circulation  of  brain,  changes  in, 

184 
Circulatory  apparatus,   action  of 
poisons  on,  88,  105 
causes  of  changes  in,  105 
changes,   indirect   results   of, 
128 
Coagulation  of  blood,   action   of 

poisons  on,  28. 
Coloring      matters     of     muscle, 

changes  in,  49 
Commutator,  Pohl's,  39 
Conductivit}'^  of  muscles,  47 
Conjunctiva,  application  of  drugs 

to,  71 
Convulsions,  mode  of  production 
of,  171 
produced  by  dyspnoea,  184 
Co-ordinated    functions,  interfer- 

rnce  with,  177 
Corpuscles  of  blood,  action  of  poi- 
sons on,  25,  28 
Cumulative  action  of  poisons,  191 
Curare,  uses  of,  193 
Current-interrupters,  97 
Czermak's  rabbit-holder,  61 


DECOMPOSITION    of    poisons, 
81,  82 
Degeneration,  fatty,  produced  by 

poisons,  161 
Deglutition,  action  of  drugs   on, 

137 
Deposit  of  drugs  in  the   system, 

80 
Depressor  nerve,  action  of  poisons 

on,  128 
Diabetes,  production  of,  by  drugs, 

161 
Digestive    apparatus,     action     of 
drugs  on,  136 
changes  in  sensibility  of, 
140 
organs,  changes  in  movements 

of,  137 
processes,  alteration  in,  144 
secretions,  alteration  in,  141 
Dog-holder,  Bernard's,  62 

Brunton's,  62 
Dogs,  modes  of  securing,  63 
Dose,  minimum  fatal,  mode  of  de- 
termining, 87 


Doses  of  poisons,  189 
Double-key,  Pohl's,  39 
Du  Bois  Reymond's  induction  coil , 
37 
key,  39 
Dysphagia, production  of,bv  drugs, 

137 
Dyspnoea,  as  a  cause  of  convul- 
sions, 134 
causes  of,  133 
production  of,  by  drugs,  131 


ELECTRODES,  46 
non-polarizable,  43 
Electro-motor   power  of   muscle, 

action  of  poisons  on,  36 
Elimination  of  poisons,  77,  82 
Emesis,  production  of,  by  drugs, 

137 
Energy  of  muscle,  measurement 

of,  48 
Excretion  of  poisons,  77,  82 
Eye,  instillations  into,  71 


FASTENING   animals,  methods 
of,  60 
Fat,  deposit  of,  in  the  body,  161 
Femoral  artery,  ligation  of,  33 
Pick's  manometer,  95 
Fistulae,  biliary,  151 

gastric,  141 

pancreatic,  143 

salivary,  145 

urinary,  154 
Forms  of  poisons,  189 
Frogs,  advantages  in  use  of,  55 

methods  of  fastening,  61 


GANGLIA  of  the  heart,  106 
Gases,   administration   of, 

through  the  lungs,  72 
application  of,  to  blood,  25 
of  blood,  action  of  poisons  on, 
30 
Gastric  fistulae,  method  of  making, 

141 
General  action  of  poisons,  55 
Generative    functions,    action    of 

drugs  on,  162 
Glands,  lachrymal,  action  of  drugs 
on,  158 
lacteal,   action   of  drugs   on, 
158 


INDEX 


199 


Glands — 

non-secretory,  action  of  drugs 

on, 158 
submaxillary,  mode  of  expos- 
ing, 148 
sweat,  action  of  drugs  on,  157 
Glandular  organs,  action  of  poi- 
sons on,  144 
Glycogenesis,  action  of  poisons  on, 

159" 
Guinea-pigs,  method  of  fastening, 
61 


HEMOGLOBIN,  action  of  poi- 
sons on,  29 
Hallucinations  produced  by  poi- 
sons, 182 
Heart,  accelerator  nerves  of,  108 
action  of  poisons  on, 
124 
action  of  poisons  on,  52,  88, 

104,  116 
antagonism  of  poisons  on,  123 
application  of  electricity  to, 

121 
ganglia  of,  106, 123 
inhibitory  nerves  of,  107 

action  of  poisons  on, 
123 
of  frogs,  mode  of  exposing,  53 
of  mammals,  mode  of  expos- 
ing, 88 
mode  of  isolating,  122 
results  of  arrest  of,  129 
Hypodermic  injections,  70 


ILIAC  artery,  ligation  of,  33 
Immunities  to  poisons,  189 
Indirect  muscular  irritability,  ex- 
amination of,  37,  40 
Induction  apparatus,  37,  45 
Infusoria,  action  of  poisons  on,  59 
Inhibition  of  reflex  actions,  181 
Inhibitory  cardiac  apparatus,  ac- 
tion of  poisons  on.  113, 
123 
ganglia,  106 
nerves,  107 
Injections  into  arteries,  67 
into  bloodvessels,  65 

poisons    unsuitable 
for,  68 
into  lymph  sacs,  70 
into  mucous  cavities,  70 


Injections — 

into  serous  sacs,  70 
into  veins.  66 
subcutaneous.  70 
Instillation  into  conjunctival  sac, 

71 
Intestinal  movements,  influence  of 

circulation  on,  130 
Intestines,  movements  of,  139 
Irritability   of   muscle,   action   of 
poisons  on,  36 
examination  of,  37,  46 
Isolated  organs,  action  of  poisons 
on,  19 


JAWS,  movements  of,  137 
Jugular  vein,  method  of  pre- 
paration, 66 


KIDNEYS,  action  of  poisons  on, 
152, 154 
elimination  of  poisons  by,  78 
Kymographion,  forms  of,  97 
use  of,  91 


LACHRYMAL  glands,  action  of 
poisons  on,  158 
Lacteal  glands,  action  of  drugs  on, 

158 
Larynx,  action  of  drugs  on,  136 
Laudanum  as  a  narcotic,  193 
Lingual  nerve,  149 
Lud wig's  and  Coats's  apparatus, 
117 
kymographion,  96 
manometer,  92 
Lungs,  administration  of  poisons 
'  through,  72 

elimination  of  poisons  by,  78 
Lymph  sacs,  injections  into,  70 


MAMMALS,  method  of  isolating 
heart  of,  122 
peculiarity  in  action  of  poisons 
on,  56 
Man,  action  of  poisons  on,  58 
Mania,  production   of,  by  drugs, 

182 
Manometer,  Tick's,  95 

for  frog,  Ludwig's,  117 

Ludwig's,  92 

mercurial,  disadvantage  of,  94 


200 


INDEX 


Marey's  comparative  myograph,  45 

tympanum  and  lever,  90 
Masticatory  movements  produced 

by  drugs,  137 
Metabolism,  influence  of  drugs  on, 

159 
Micrococci,  action  of  poisons  on, 

60 
Milk  secretion,  influence  of  drugs 

on,  158 
Morphia  as  a  narcotic,  193 
Motor  nerves,  action  of  poisons  on, 

50 
Mucous  cavities,  injections  into,  70 
Miiller's  valves,  74 
Muscles,  action  of  poisons  on,  31, 
164 
application  of  gases  and  vapors 

to,  32 
changes  in  coloring  matters  of, 

49 
chemical  changes  in,  48 
conductivity  of,  47 
electro-motive  power  of,  36 
energy  of,  measurement  of,  48 
mechanical  stimulation  of,  47 
Muscular  irritability,  action  of  poi- 
sons on,  36 
examination  of,  37,  46 
Myographion,  Marey's,  45 
Pfliiger's,  43 


NARCOSIS,  methods  of  produc- 
ing, 192 
production  of,  by  drugs,  183 
Nerves,  accelerator  cardiac,  108 
action  of  poisons  on,  49,  169 
chorda  tympani,  149 
current,  negative  variation  of, 

51 
endings,  action  of  poisons  on, 

172 
inhibitory  cardiac,  107 
lingual,  149 
motor,  action  of  poisons  on, 

50 
muscle  preparation,  36 
sensory,  action  of  poisons  on, 

52,  172 
trunks,  action  on,  170 
Nervous  system,  action  of  poisons 

on,  169,  175 
Non-polarizable  electrodes,  43 
Nutrition,  influence  of  drugs  on, 
159 


ORGANS,  isolated,  action  of  poi- 
sons on,  19 
Oxidation  of  poisons,  83 

processes,  energy  of,  160 
Ozone  of  blood,  action  of  poisons 
on,  30 


PANCREATIC  flstulfe,  143 
Paralysis,  mode  of  production 
of,  46,  50,  170,  172,  175 
Peristalsis,  action  of  drugs  on,  139 
Pfliiger's  myographion,  43 
Pharmacology,  methods  of  study 
of,  15,"  17 
object  of,  15 
scope  of,  13 
Pithing,  method  of  performing,  53 
Pneumogastric,  action  of  poisons 

on,  114 
Pohl's  commutator,  39 
Poisons,  absorption  of,  64 

action  of,  on  circulatory  appa- 
ratus, 88 
on  isolated  organs,  19 
administration  of,  63 
changes  in,  77,  80 
definition  of,  13 
elimination  of,  77 
explanation  of  symptoms  pro- 
duced by,  85 
general  action  of,  55,  85 
local  action  of,  85 
oxidation  of,  83 
Protoplasm,  action  of  poisons  on, 

59 
Pulse,  action  of  drugs  on,  113 
and    blood-pressure,    relation 
between,  125 
Pupil,  action  of  drugs  on,  165 


"pABBIT-HOLDER,    Czermak's, 

Rabbits,  mode  of  fastening,  61 

Reaction  of  blood,  modes  of  test- 
ing, 23 

Recovery  from  poisoning,  mode  of, 
86 

Reflex  action,  action  of  drugs  on, 
177 
inhibition  of,  181 

Renal  secretion,  action  of  drugs 
on,  152 

Reproductive  functions, alterations 
in, 162 


INDEX. 


201 


Respiratory   apparatus,  action   of 
drugs  on,  76,  130 
centre,  reduction  in  irritability 

of,  134 
changes,   modes  of  studying, 

131 
movement,  cessation  of,  134 
changes  in  frequency  of, 

135 
effects      of      interference 
with,  133 
muscles,  paralysis  of,  135 
Kigor  of  muscles,  recognition  of,  49 
Roy's  apparatus  for  frog's  heart, 
119 


SALIVARY     fistulas,    mode    of 
making,  145 
secretion,  action  of  poisons  on, 
145,  150 
Salts,  decomposition  of,  81 
Sanderson's  cardiograph,  89 
Sartorius  of  frog,  action  of  poisons 

on,  46 
Secretions,  action  of  poisons  on, 
141 
elimination  of  poisons  in,  79 
Securing  animals,  methods  of,  60 
Selection  of  animals,  55 
Sensibility   of   alimentary    canal, 

140 
Sensory  functions,  action  of  drugs 
on,  182 
nerves,  action  of  poisons   on, 
173 
Serous  sacs,  injection  into,  70 
Setschenow's    centre,     action    of 

drugs  on,  181 
Sinus  venosus,  action  of  poisons 

on, 121 
Solvents  of  poisons,  189 
Sphygmograph,  use  of,  91 
Spleen,  action  of  drugs  on,  159 
Spring  manometer,  Fick's,  95 
Stomach,  injection  into,  70 

movements  of,  137 
Subcutaneous  injections,  70 
Submaxillary  gland,  mode  of  ex- 
posing, 148 
Sweat  glands,  action   of   poisons 
on,  157 
secretion,  influence  of  nerves 
on,  157 


Symptoms,    mode    of    observing, 
,       86 
produced  by  poisons,  explana- 
tion of,  85 
Syncope,  production  of,  by  drugs, 
183 


TAMBOUR,  Marey's,  90 
Temperature,  alterations    in, 
164 
Time  markers,  97 
Tissue  metabolism,  action  of  drugs 

on,  159 
Tracings  of  blood-pressure,  103 
tabulation  of,  104 
Tympanum    and    lever,    Marey's, 
90 


URINARY  fistuliB,  154 
secretion,  action  of  drugs 
on,  152 
Uterine  contractions,  influence  of 
circulation  on,  130 
production  of,  by  drugs, 
163 
Uterus,  action  of  poisons  on,  163 


VALVES,  MUller's,  74 
Vapors,     administration     of, 
through  lungs,  72 
Vascular  apparatus,  action  of  poi- 
sons on,  125 
Vaso-motor  centre,  110,  125 

action   of   drugs    on, 
127 
system,  110 

action  of   drugs    on, 
126 
Veins,  advantages   for  injections, 
65 
injections  into,  66 
jugular,  mode  of  preparation, 
66 
Venosity  of  blood,  causes  of,  133 
Ventricles,  action  of  poisons  on, 

121 
Vibrios,  action  of  poisons  on,  60 
Vomiting,  mode  of  production  of, 
138 
production  of,  by  drugs,  137 
share  of  the  stomach  in,  138 


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Henry  C.  Simes,  M.D  ,  and  J.  William  White,  M.D.  In  one  8vo. 
volume  of  461  pages,  with  84  illustrations.     Cloth,  $.3  75. 

nULLERIER  (A.)  AN  ATLAS  OF  VENEREAL  DISEASES.  Trans- 
lated  and  edited  by  Freeman  J.  BuMSTEAD,  M.D. ,  LL.D.  A  large 
quarto  volume  of  .328  pages,  with  26  plates  containing  about  150 
figures,  beautifully  colored,  many  of  them  life-size.     Cloth,  $17. 

T) ALTON  (JOHN  C.)  DOCTRINES  OF  THE  CIRCULATION  OF 
THE  BLOOD.    In  one  handsome  12mo.  vol.  of  293  pp.    Cloth,  $2. 

A  TREATISE  ON  HUMAN  PHYSIOLOGY.     Seventh  edition, 

thoroughly  revised,  and  greatly  imp^-oved.  In  one  very  handsome 
8vo.  vol.  of  722  pages,  with  252  illustrations.  Cloth,  $5;  lea- 
ther,  $6. 

"HANA  (JAMES  D.)  THE  STRUCTURE  AND  CLASSIFICATION  OF 
ZOOPHYTES.    Withillust.onwood.  Inoneimp.4to.vol.    CI. ,$4. 

TjAVENPORT  (F.  H.)  DISEASES  OP  WOMEN.  A  Manual  of  Non- 
Surgical  Gynaecology.  For  the  use  of  Students  and  General  Prac- 
titioners In  one  handsome  ]2mo.  volume  of  306  pages  with  105 
illustrations.     Cloth,  $1  50.     Just  ready. 

T\AVIS(F.H.)  LECTURES  ON  CLINICAL  MEDICINE.  Second 
edition     In  one  12mo.  volume  of  287  pages.     Cloth,  $175. 

DELA  BECHE'S  GEOLOGICAL  OBSERVER.  Inone  large  Svo.vo 
of  700  pages,  with  300  illustrations.  Cloth,  $4. 
■rvRAPER  (JOHN  C.)  MEDICAL  PHYSICS.  A  Text-book  for  Stu- 
dents  and  Practitioners  of  Medicine.  In  one  handsome  octavo  vol- 
ume of  734  pages,  with  376  illustrations.  Cloth,  $4. 
DRUITT  (ROBERT).  THE  PRINCIPLES  AND  PRACTICE  OF 
MODERN  SURGERY.  A  new  American  from  the  12th  London 
edition,  edited  by  Stanley  Boyd,  F.R  C.S.  In  one  large  octavo 
volume  of  965  pages,  with  373  illustrations.    Cloth,  $4  ;  leather,  $5. 

DUNCAN  (J.  MATTHEWS).  CLINICAL  LECTURES  ON  THE  DIS- 
EASES  OF  WOMEN.  Delivered  in  St.  Bartholomew's  Hospital. 
In  one  octavo  volume  of  175  pages.    Cloth,  $1  50. 

DTJNGLISON  (ROBLEY),  MEDICAL  LEXICON;  A  Dictionary  of 
Medical  Science.  Containing  a  concise  explanation  of  the  various 
subjects  and  terms  of  Anatomy,  Physiology,  Pathology,  Hygiene, 
Therapeutics,  Pharmacology,  Pharmacy,  Surgery,  Obstetrics,  Medi- 
ealJurisprudence  and  Dentistry  ;  noticesof  Climate  and  of  Mineral 
Waters  ;  Formulae  forOffieinal,  Empirical  and  Dietetic  Preparations; 
with  the  accentuation  and  Etymology  of  the  Terms,  and  the  French 
and  other  Synonymes.  Edited  by  R.  J.  Dunglison,  M.D,  In  one 
very  large  royal  8vo.  vol.  of  1139  pages.  Cloth,  $6  50  j  leather, 
$7  50;   half  Russia,  $8. 

EDES'  TEXT-BOOK  OF  THERAPEUTICS  AND  MATERIA  MEDICA. 
In  one  8vo.   volume  of  544  pages.     Cloth,   $3  50 ;    leather,  $4  50. 
EDIS  (ARTHUR  W.)      DISEASES  OF  WOMEN.     A  Manual  for  Stu- 
dents and  Practitioners.      In  one  handsome  8vo.  vol.  of  576  pp., 
with  148  illustrations.     Cloth,  $3  ;  leather,  $4. 


6  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

TJLLIS  (GEORGE  VINEE).  DEMONSTRATIONS  IN  ANATOMY. 
Being  a  Guide  to  the  Knowledge  of  the  Human  Body  by  Dissection. 
From  the  eighth  and  revised  English  edition.  In  one  octavo  vol. 
of  716  pages,  with  249  illustrations.     Cloth.  $4  25  ;  leather.  $5  25. 

y  IMET  (THOMAS  ADDIS).     THE  PRINCIPLES  AND  PRACTICE 

^     OF  GYNECOLOGY,  for  the  use  of  Students  and  Practitioners. 

Third  edition,  enlarged  and  revised.     In  one  large  8vo.  volume  of 

880  F^ges,  with  150  original  illustrations.     Cloth,  $5;  leather,  $6. 

piICHSEN  (JOHN  E.)  THE  SCIENCE  AND  ART  OF  SURGERY. 
A  new  American,  from  the  eighth  enlarged  and  revised  London 
edition.  In  two  large  octavo  voluires  containing  2316  pages,  with 
984illus.     Cloth,  $9;  leather,  $11. 

pARQUHARSON    (ROBERT).      A    GUIDE   TO    THERAPEUTICS. 

Fourth  American  frcm  Fourth  English  edition,  revised  by  Frank 
Woodbury,  MD.    In  one  12mo.  volume  of  581  pages.   Cloth,  $2  50. 

"pENWICK  (SAMUEL).  THE  STUDENTS'  GUIDE  TO  MEDICAL 
DIAGNOSIS.  From  the  third  revised  and  enlarged  London  edi- 
tion.   In  one  royal  12mo.  volume  of  328  pages.    Cloth,  $2  25. 

piNLAYSON  (JAMES).  CLINICAL  DIAGNOSIS.  A  Handbook  for 
Students  and  Practitioners  of  Medicine.  Second  edition.  In  one 
12mo.  volume  of  682  pages,  with  158  illustrations.     Cloth,  $2  50. 

pLINT    (AUSTIN).    A    TREATISE  ON  THE  PRINCIPLES    AND 

^      PRACTICE  OF   MEDICINE.      Sixth  edition,  thoroughly  revised 

and  largely  rewritten  by  the  Author,  assisted  by  William  H.  Welch, 

MD  ,  and  Austin  Flint,  Jr.,  M.D.     In  one  large  8vo.  volume  of 

1160  pages,  with  illustrations.     Cloth,  $5  50  ;  leather,  $6  50. 

A  MANUALOF  AUSCULTATION  AND  PERCUSSION;  of  the 

Physical  Diagnosis  of  Diseases  of  the  Lungs  and  Heart,  and  of  Tho- 
racic Aneurism.  Fourth  edition,  revised  and  enlarged.  In  one 
handsome  12mo.  volume  of  240  pages.     Cloth,  $1  75. 

A  PRACTICALTREATISE  ON  THE  DIAGNOSIS  AND  TREAT- 
MENT OF  DISEASES  OF  THE  HEART.  Secondedition, enlarged. 
In  one  octavo  volume  of  550  pages.     Cloth,  $4  00. 


A  PRACTICAL  TREATISE  ON  THE  PHYSICAL  EXPLORA- 
TION OF  THE  CHEST,  AND  THE  DIAGNOSIS  OF  DISEASES 
AFFECTING  THE  RESPIRATORY  ORGANS.  Second  and  revised 
edition.     In  one  octavo  volume  of  591  pages.     Cloth,  $4  50. 

MEDICAL  ESSAYS.   In  one  12mo.  vol.,  pp.  210.    Cloth,  $138. 

ON    PHTHISIS:    ITS    MORBID    ANATOMY,    ETIOLOGY, 

KTC.     A  series  of  Clinical  Lectures.     In  one  8vo.  volume  of  442 
pages.     Cloth,  $3  50. 

'OLSOM  (C.  F.)  An  Abstract  of  Statutes  of  U.  S.  on  Custody  of  the 
Insane.  In  one  8vo.  vol.  of  108  pp.  Cloth,  $1  60.  Also  bound 
with  Clouston  on  Ivsavity. 


LEA  BROTHERS  &  CO.'S  PUBLICATIONS.  7 

pOSTER  (MICHAEL).  A  TEXT-BOOK  OF  PHYSIOLOGY.  Fourth 
American  from  the  fifth  English  edition,  edited  byE.T.  Reichert, 
M.D.  In  one  large  12mo.  vol.  of  about  925  pages,  with  about  300 
illustrations.     Preparing. 

pOTHERGILL'S  PRACTITIONER'S  HANDBOOK  OF  TREATMENT. 
New  (third)  edition.  In  one  handsome  octavo  volume  of  664  pages. 
Cloth,  $3  75  ;  leather,  $4  75. 

pO WNES  (GEORCJE) .  A  MANUAL  OF  ELEMENTARY  CHEMISTRY 

•*■  (INORGANIC  AND  ORGANIC).  New  edition.  Embodying  Watts' 
Physical  and  Inorganic  Chemistry.  In  one  royal  12mo.vol.  of 
1061  pages,  with  168  illus.,  and  one  colored  plate.  Cloth,  $2  75; 
leather,  $3  25. 

pox  (TILBURY)  and  T.  COLCOTT.  EPITOME  OF  SKIN  DIS- 
EASES,  with  Formulae.  For  Students  and  Practitioners.  Third 
Am.  edition,  revised  by  T.  0.  Fox.  In  one  small  12mo.  volume 
of  238  pages.     Cloth,  $1  25. 

pRA^NKLAND  (E  )  and  JAPP  (F.  R.)  INORGANIC  CHEMISTRY. 
In  one  handsome  octavo  vol.  of  677  pages,  with  51  engravings  and 
2  plates.     Cloth,  $3  75;  leather,  $4  75. 

pULLER  (HENRY).    ON  DISEASES  OF  THE  LUNGS  AND  AIR 

"*•  PASSAGES.  Their  Pathology,  Physical  Diagnosis,  Symptoms  and 
Treatment.  From  2d  Eng.  ed     In  1  8vo.  vol.,  pp.  475.   Cloth,  $3  50. 

piBNEY  (V.  P.)  ORTHOPEDIC  SURGERY.  For  the  use  of  Prae- 
titioners  and  Students.     In  one  8vo.  vol.  profusely  illus.     Prepg. 

piBSON'S  INSTITUTES  AND  PRACTICE  OF  SURGERY.  In  two 
octavo  volumes  of  965  pages,  with  34  plates.     Leather,  $6  50. 

pLUGE  (GOTTLIEB).  ATLAS  OF  PATHOLOGICAL  HISTOLOGY. 
Translated  by  Joseph  Leidy,  M.D.,  Professor  of  Anatomy  in  the 
University  of  Pennsylvania,  &c.  In  one  imperial  quarto  volume, 
with  320  copperplate  figures,  plain  and  colored.    Cloth,  $4 

pOULD  (A.  PEARCE).  SURGICAL  DIAGNOSIS.  In  one  12mo. 
vol.  of  589  pages.    Cloth,  $2.    See  Slitdents'^  Series  of  Manuals,  p.  14. 

pRAY  (HENRY).    ANATOMY,  DESCRIPTIVE  AND  SURGICAL. 

^  Edited  by  T.  Pickering  Pick,  F.R.C.S.  A  new  American,  from  the 
eleventh  English  edition,  thoroughly  revised,  with  additions,  by 
W.  W.  Keen,  M.D.  To  which  is  added  Holden's  "Landmarks, 
Medical  and  Surgical."  In  one  imperial  octavo  volume  of  1098 
pages,  with  685  large  and  elaborate  engravings  on  wood.  Cloth,  $6  ; 
leather,  $7  ;  very  handsome  half  Russia,  raised  bands,  $7  50.  The 
same  edition  is  also  issued  with  veins,  arteries,  and  nerves  distin- 
guished in  colors.  Price,  cloth,  $7  25  ;  leather,  $8  25  ;  half  Rus- 
sia,  $8  75. 

GRAY  (LANDON  CARTEl^).  A  PRACTICAL  TREATISE  ON  THE 
DISEASES  OP  THE  NERVOUS  SYSTEM.  In  one  handsome 
octavo  volume  of  about  600  pages.     Preparing. 

GREEN  (T.  HENRY).  AN  INTRODUCTION  TO  PATHOLOGY  AND 
MORBID  ANATOMY.  New  (sixth)  American,  from  the  seventh 
London  edition.  In  one  handsome  octavo  volume  of  540  pages, 
with  167  illustrations.     Cloth,  $2  75.     Just  ready. 

GREENE  (WILLIAM  H.)  A  MANUAL  OF  MEDICAL  CHEMISTRY. 
For  the  Use  of  Students.  Based  upon  Bowman's  Medical  Chem- 
istry. In  one  12mo.  vol.  of  310  pages,  with  74  illus.    Cloth,  $1  73. 


8  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

pRIFFITH  (ROBERT  E.)     A   UNIVERSAL  FORMULARY,  CON- 
^    TAINING  THE  METHODSOFPREPARING  AND  ADMINISTER- 
ING OFFICINAL  ANDOTHER  MEDICINES.  Third  and  enlarged 
edition.    Edited  by  John  M.  Maisch,  Phar.D.     In  one  large  8to. 
vol.  of  775  pages,  double  columns.     Cloth,  $4  50  ;  leather,  $5  60. 
nROSS(SAMUELD.)  A  SYSTEM  OF  SURGERY, PATHOLOGICAL, 
^     DIAGNOSTIC,  THERAPEUTIC  AND  OPERATIVE.     Sixth  edi- 
tion,  thoroughly  revised.    In  two  imperial  octavo  volumes  contain- 
ing 2382  pages,  with  1623  illustrations.    Strongly  bound  in  leather, 
raised  bands,  $15. 

A   PRACTICAL  TREATISE  ON  THE   DISEASES,    INJU- 

ries  and  Malformations  of  the  Urinary  Bladder,  the  Prostate  Gland 
and  the  Urethra.  Third  edition,  thoroughly  revised  and  much 
condensed,  by  Samuel  W.  Gross,  M.D.  In  one  octavo  volume  of 
574  pages,  with  170  illus.     Cloth,  $4  50. 

A  PRACTICAL  TREATISE  ON  FOREIGN  BODIES  IN  THE 

AIR  PASSAGES.    Inone  Svo.  vol.  of  468  pages.    Cloth,  $2  75. 
pROSS   (SAMUEL   W.)      A   PRACTICAL   TREATISE   ON    IMPO- 
^    TENCE,    STERILITY,    AND    ALLIED   DISORDERS   OF    THE 
MALE  SEXUAL  ORGANS.     New  (third)  edition.     In  one  hand- 
some octavo  vol.  of  163  pages,  with  16  illustrations.     Cloth,  $1  50. 
TTABERSHON  (S.  0.)     ON  THE  DISEASES  OF  THE  ABDOMEN, 
^   AND  OTHER  PARTS  OF  THE  ALIMENTARY  CANAL.    Second 
American,  from  the  third  English  edition.     In  one  handsome  Svo. 
volume  of  554  pages,  with  illus.     Cloth,  $3  50. 
TTAMILTON  (ALLAN  McLANE).     NERVOUS  DISEASES,   THEIR 
""•    DESCRIPTION  AND  TREATMENT.    Second  and  revised  edition. 
In  one  octavo  volume  of  598  pages,  with  72  illustrations.   Cloth,  $4. 
"□"AMILTGN    (FRANK  H.)    A  PRACTICAL  TREATISE  ON  FRAC- 
^    TURES  AND  DISLOCATIONS.    Seventh  edition,  thoroughly  re- 
vised.    In  one  handsome  Svo.  vol.  of  998  pages,  with  352  illustra- 
tions.    Cloth,  $5  50;  leather,  $6  50. 
ARTSHORNE  (HENRY).    ESSENTIALS  OF  THE  PRINCIPLES 
AND  PRACTICE  OF  MEDICINE.     Fifth  edition.    In  one  12mo. 
volume,  669  pages,  with   144  illustrations.     Cloth,    $2   75;    half 
bound,   $3. 

A  HANDBOOK  OF  ANATOMY  AND  PHYSIOLOGY.     In  one 

]2mo.  volume  of  310  pages,  with  220  illustrations.     Cloth,  $1  75. 

A   CONSPECTUS   OF   THE   MEDICAL   SCIENCES.      Com- 


H 


prising  Manuals  of  Anatomy,  Physiology,  Chemistry,  Materia 
Medica,  Practice  of  Medicine,  Surgery  and  Obstetrics.  Second 
edition.  In  one  royal  12mo,  volume  of  1028  pages,  with  477  illus- 
trations. Cloth,  $4  25  ;  leather,  $5  00. 
TTERMANN  (L.)  EXPERIMENTAL  PHARMACOLOGY.  A  Hand- 
book  of  the  Methods  for  Determining  the  Physiological  Actions  of 
Drugs.  Translated  by  Robert  Meade  Smith,  M.D.  In  one  12mo  vol, 
of  199  pages,  with  32  illustrations.  Cloth,  $1  50. 
ILL  (BERKELEY).  SYPHILIS  AND  LOCAL  CONTAGIOUS  DIS- 
ORDERS     In  one  Svo.  volume  of  479  pages.     Cloth.  $3  25. 


H 


LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 


ITILLIER  (THOMAS).  A  HANDBOOK  OF  SKIN  DISEASES.  2d  ed. 
In  one  royal  12mo.  vol.  of  353  pp.,  with  two  plates.     Cloth,  $2  25. 

TTOBLYN  (RICHARD  D.)    A  DICTIONARY  OF  THE  TERMS  USED 

•*-*■  IN  MEDICINE  AND  THE  COLLATERAL  SCIENCES.  In  one 
12mo.  vol.  of  520  double-columned  pp.    Cloth,  $1  50  ;  leather,  $2 

TTODGE  (HUGH  L.)     ON  DISEASES  PECULIAR  TO  WOMEN,  IN- 

^  CLUDING  DISPLACEMENTS  OF  THE  UTERUS.  Second  and 
revised  edition.     In  one  8vo.  volume  of  519  pages.     Cloth,  $4  50. 

THE  PRINCIPLES  AND  PRACTICE  OF  OBSTETRICS.  In  one 

large  4to.  vol.  of  542  double-columned  pages,  illustrated  with  large 
lithographic  plates  containing  159  figures  from  original  photographs, 
and  110  woodcuts.     Strongly  bound  in  cloth,  $14. 

TTOFFMANN   (FREDERICK)   AND  POWER  (FREDERICK  B.)     A 

"'-'■  MANUAL  OF  CHEMICAL  ANALYSIS,  as  Applied  to  the  Examina- 
tion  of  Medicinal  Chemicals  and  their  Preparations.  Third  edition, 
entirely  rewritten  and  much  enlarged.  In  one  handsome  octavo 
volume  of  621  pages,  with  179  illustrations.     Cloth,  $4  25. 

TTOLDEN  (LUTHER) .  LANDMARKS,  MEDICAL  AND  SURGICAL. 
From  the  third  English  edition.  With  additions,  by  W.  W.  Keen, 
M.D.    In  one  royal  12mo.  vol.  of  148  pp.    Cloth,  $1. 

TTOLLAND  (SIR  HENRY).  MEDICAL  NOTES  AND  REFLECTIONS. 
From  3d  English  ed.     In  one  Svo.  vol.  of  493  pp.     Cloth,  $3  50. 

TTOLMES  (TIMOTHY).  A  SYSTEM  OF  SURGERY.  With  notes  and 
additions  by  various  American  authors.  Edited  by  John  H.  Packard, 
M.D.  In  three  very  handsome  Svo.  vols,  containing  3137  double- 
columned  pages,  with  979  woodcuts  and  13  lithographic  plates. 
Cloth,  $18;  leather,  $21;  very  handsome  half  Russia,  raised  bands, 
$22  50.     For  sale  by  stibscription  only. 

A  TREATISE  ON  SURGERY.     Its  Principles  and  Practice.    A 

new  American  from  the  fifth  English  edition.  Edited  by  T.  Pickering 
Pick,  F.R.C.S.  In  one  handsome  octavo  volume  of  1008  pages,  with 
428  engravings.    Cloth,  $6  ;  leather,  $7.     Jrist  ready. 

TTORNER  (WILLIAM  E.)  SPECIAL  ANATOMY  AND  HISTOLOGY. 
Eighth  edition,  revised  and  modified.  In  twolarge8vo.  vols,  of  1007 
pages,  containing  320  woodcuts.     Cloth,  $6. 

TTUDSON  (A.)  LECTURES  ON  THE  STUDY  OF  FEVER.  In 
one  octavo  volume  of  308  pages.     Cloth,  $2  50. 

■CTUTCHINSON  (JONATHAN).  SYPHILIS.  In  one  pocket  size  12mo. 
volume  of  542  pagas,  with  8  chromo-lithographic  plates.  Cloth, 
$2  25.  See  Series  of  Clinical  Manuals,  p.  13. 
DE  (JAMES  NEVINS).  A  PRACTICAL  TREATISE  ON  DISEASES 
OF  THE  SKIN.  New  (second)  edition.  In  one  handsome  octavo 
volume  of  676  pages,  with  85  engravings  and  2  colored  plates. 
Cloth,  $4  50  ;  leather,  $5  50. 

TONES  (C.  HANDFIELD).    CLINICAL  OBSERVATIONS  ON  FUNC- 

"  TIONAL  NERVOUS  DISORDERS.  Second  American  edition.  In 
one  octavo  volume  of  340  pages.     Cloth,  $3  25. 

TULER  (HENRY).      A  HANDBOOK  OF  OPHTHALMIC   SCIENCE 

"  AND  PRACTICE.  In  one 8vo.  volume  of  460  pages,  with  125  wood- 
cuts, 27  chromo-lithographic  plates  test  types  of  Jaeger  and  Snellen 
and  Holmgren's  Color-blindness  test.    Cloth,  $4  50;  leather,  $5  50. 


W 


10  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

"piNG  (A.  F.  A.)  A  MANUAL  OF  OBSTETHICS.  New  (fourth) 
edition.  In  one  12mo.  volume  of  432  pages,  with  141  illustrations. 
Cloth,  $2  50.     Just  ready 

TTLEIN  (E  )  ELEMENTS  OF  HISTOLOGY.  Fourth  edition.  In 
one  pocket-size  12mo.  volume  of  376  pages,  with  194  engravings. 
Cloth,  $1  75.     Jn St  ready.     S*;e  Stude?its^  Series  of  Manuals,  p.  14. 

TANDIS  (HENRY  G)  THE  MANAGEMENT  OF  LABOR.  In  one 
handsome  12mo.  volume  of  329  pages,  with  28  illus.     Cloth,  $1   75. 

T  A  ROCHE  (R.)    YELLOW  FEVER.    In  two  8vo.  vols,  of  1468  pages. 

■*-'     Cloth,  $7. 

PNEUMONIA.    In  one  8vo.  vol.  of  490  pages.     Cloth,  $3. 

T  AURENCE  (J.  Z.)  AND  MOON  (ROBERT  C.)      A  H.\NDY-BOOK 

•^  OF  OPHTHALMIC  SURGERY.  Second  edition,  revised  by  Mr. 
Laurence.     In  one  8vo.  vol.  pp.  227,  with  66  illus.     Cloth,  $2  75. 

T  AWSON  (GEORGE) .  INJURIES  OF  THE  EYE,  ORBIT  AND  EYE- 
LIDS. From  the  last  English  edition.  In  one  handsome  octavo 
volume  of  404  pages,  with  92  illustrations.  Cloth,  $3  50. 
EA  ( HENRY  C.)  SUPERSTITION  AND  FORCE  ;  ESSAYS  ON  THE 
WAGER  OF  LAW,  THE  WAGER  OF  BATTLE,  THE  ORDEAL 
AND  TORTURE.  Third  edition,  thoroughly  revised  and  greatly 
enlarged.    In  onehandsomeroyal  12mo.  vol.  pp.  552.    Cloth,  $2  50. 

—  STUDIES  IN  CHURCH  HISTORY.  The  Riseof  the  Temporal 
Power — Benefit  of  Clergy — Excommunication.  New  edition.  In 
one  handsome  12mo.  vol.  of  605  pp.     Cloth,  $2  50. 

—  AN  HISTORICAL  SKETCH  OF  SACERDOTAL  CELIBACY 


L 


IN  THE  CHRISTIAN  CHURCH.  Second  edition.  In  one  hand- 
some  octavo  volume  of  684  pages.     Cloth,  $4  50. 

TEE  rHENRY)  ON  SYPHILIS.     In  one  8vo   volume  of  246  pages. 

-*-•     Cloth,  $2  25. 

T  EHMANN  (0.  G.)  A  MANUAL  OF  CHEMICAL  PHYSIOLOGY. 
In  one  8vo.  vol.  of  327  pages,  with  41  woodcuts.    Cloth,  $2  25. 

T  EISHMAN  (WILLIAM).  A  SYSTEM  OF  MIDWIFERY.  Includ- 
ing the  Diseases  of  Pregnancy  and  the  Puerperal  State.  Third 
American,  from  the  third  English  edition.  With  additions,  by 
J.  S.  Parry,  M.D.  In  one  octavo  volume  of  740  pages,  with  205 
illustrations.     Cloth,  $4  50  ;  leather,  $5  50. 

TUCAS  (CLEMENT).  DISEASES  OF  THE  URETHRA.  Preparing. 
See  Series  of  Clinical  Manuals,  p.  13. 

T  UDLOW  (J.  L.)    A  MANUAL  OF  EXAMINATIONS  UPON  ANAT- 

•'-'  OMY,  PHYSIOLOGY,  SURGERY,  PRACTICE  OF  MEDICINE, 
OBSTETRICS,  MATERIA  MEDICA,  CHEMISTRY,  PHARMACY 
AND  THERAPEUTICS.  To  which  is  added  a  Medical  Formulary. 
Third  edition.  In  one  royal  12mo.  volume  of  816  pages,  with  370 
woodcuts.     Cloth,  $3  25;   leather,  $3  75. 

T  YONS  (ROBERT  D.)     A  TREATISE  ON  FEVER.    In  one  octavo 

■*-'     volume  of  362  pages.     Cloth,  $2  25. 

AISCH  (JOHN  M.)  A  MANUAL  OF  ORGANIC  MATERIA  MED- 
ICA.  New  (third)  edition.  In  one  handsome  l2mo.  volume  of 
623  pages,  with  257  beautiful  illustrations.    Cloth,  $3. 


M 


LEA  BROTHERS  &  CO.'S  PUBLICATIONS.       11 

TUTARSH  (HOWARD).  DISEASES  OF  THE  JOINTS.  In  one  12mo. 
volume  of  468  pages,  with  64  illustrations  and  a  colored  plate. 
Cloth,  $2.      See  Series  of  Clinical  Mam/als,  p.  1.3. 

TWrAY  (C.  H.)  MANUAL  OF  THE  DISEASES  OF  WOMEN.  For  the 
use  of  Students  and  Practitioners.  In  one  12mo.  volume  of  342 
pages.     Cloth,  $1  75. 

TUTEIGS  (CHAS.  D.)    ON  THE  NATURE,  SIGNS  AND  TREATMENT 

•^■'■^  OF  CHILDBED  FEVER.    In  on«  8vo.  vol.  of  346  pages.    Cloth,  $2. 

TWriLLER  (JAMES).  PRINCIPLES  OF  SURGERY.  Fourth  American, 
from  the  third  Edinburgh  edition.  In  one  large  octavo  volume  of 
688  pages,  with  240  illustrations.     Cloth,  $3  75. 

TWriLIER  (JAMES).  THE  PRACTICE  OF  SURGERY.  Fourth 
American,  from  the  last  Edinburgh  edition.  In  one  large  octavo 
volume  of  682  pages,  with  364  illustrations.     Cloth,  $3  75. 

TUriTCHELL  (S.  WEIR).     LECTURES   ON  NERVOUS   DISEASES, 

•""■  ESPECIALLY  IN  WOMEN.  Second  edition.  In  one  12mo.  vol- 
ume of  288  pages.     Cloth,  $1   75. 

TyrORRIS  (HENRY).  SURGICAL  DISEASES  OF  THE  KIDNEY. 
12mo.,  554  pages,  40  woodcuts,  and  6  colored  plates.  Cloth,  $2  25. 
See  Series  of  Clinical  Mainials,  p.  13. 

TWrULLER  (J.)  PRINCIPLES  OF  PHYSICS  AND  METEOROLOGY. 
In  one  large  8vo.  vol.  of  623  pages,  with  538  cuts.     Cloth,  $4  50. 

•M-EILL  (JOHN)  AND  SMITH  (FRANCIS  G.)     A  COMPENDIUM  OF 

^  THE  VARIOUS  BRANCHES  OF  MEDICAL  SCIENCE.  In  one 
handsome  12mo.  volume  of  974  pages,  with  374  woodcuts.  Cloth, 
$4  J  leather,  raised  bands,  $4  75, 

'M'ETTLESHIP'S  STUDENT'S  GUIDE  TO  DISEASES  OF  THE  EYE. 
New  (third)  edition.  In  one  royal  12mo.  volume  of  479  pages,  with 
164  illustrations,  test  types  and  formulae.     Cloth,  $2. 

"M"0IIRIS  AND  OLIVER  ON  THE  EYE.  In  one  8vo.  volume  of  about 
500  pages,  with  illustrations.     Prep%ri7ig. 

QWEN  (EDMUND).  SURGICAL  DISEASES  OF  CHILDREN.  12mo., 
625  pages,  85  woodcuts,  and  4  colored  plates.  Cloth,  $2.  See  Series 
of  Clinical  Manuals,  p.  13. 

pARRISH  (EDWARD) .  A  TREATISE  ON  PHARMACY.  With  many 
Formulae  and  Prescriptions.  Fifth  edition,  enlarged  and  thoroughly 
revised  by  Thomas  S.  Wiegand,  Ph.G.  In  one  octavo  volume  of 
1093  pages,  with  257  illustrations.     Cloth;  $5  ;  leather,  $6. 

pARRY  (JOHN  S.)  EXTRA- UTERINE  PREGNANCY,  ITS  CLIN- 
ICAL HISTORY,  DIAGNOSIS,  PROGNOSIS  AND  TREAT- 
MENT.    In  one  octavo  volume  of  272  pages.     Cloth,  $2  50. 

pARVIN  (THEOPHILTJS).  THE  SCIENCE  AND  ART  OF  OBSTET- 
RICS.  In  one  handsome  8vo.  volume  of  697  pages,  with  214  en- 
gravings and  a  colored  plate.  Cloth,  $4  25  ;  leather,  $5  25. 
PAVY  (F.  W.)  A  TREATISE  ON  THE  FUNCTION  OF  DIGESTION, 
ITS  DISORDERS  AND  THEIR  TREATMENT.  From  the  second 
London  edition.     In  one  octavo  volume  of  238  pages.    Cloth,  $2. 

PAYl^E  (JOSEPH  FRANK).  A  MANUAL  OF  GENERAL  PATHOL- 
ogy.  Designed  as  an  Introduction  to  the  Practice  of  Medicine. 
Handsome  octavo  volume  nf  524  pages  with  153  engravings  and  1 
colored  plate.     Cloth,  $3  50. 


12  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

pEPPEE  (A.  J.)     FORENSIC  MEDICINE.     In  press.     See  ^ttcdents' 
Series  of  Manuals,  p.  14. 

SURGICAL  PATHOLOQ r.    In  one  12mo.  volume  of  5M  pages, 


with  81  illus.    Cloth,  $2.     See  Students^  Series  of  Manuals,  p.  14. 
piCK    (T.    PICKERING).      FRACTURES    AND     DISLOCATIONS. 

In  one  12mo.  volume  of  530  pages,  with  93  illustrations.    Cloth,  $2. 

See  Series  of  Clinical  Manuals,  p.  13. 
piRRIE  (WILLIAM).  THE  PRINCIPLES  AND  PRACTICE  OF  SUR- 
GERY.   In  one  handsome  octavo  volume  of  780  pages,  with  316 

illustrations.    Cloth,  $3  75. 
pLAYFAIR  (W.  S  )     A  TREATISE  ON  THE  SCIENCE  AND  PRAC- 
^     TICE  OF  MIDWIFERY.     New  (fifth)  American  from  the  seventh 

English  edition.      Edited,  with  additions,  by  R.  P.  Harris,  M.D. 

In  one  octavo  volume  of  664  pages,  with  207  woodcuts  and  five 

plates.     Cloth,  $4;   leather,  $5.     Just  ready. 
THE  SYSTEMATIC  TREATMENT  OF  NERVE    PROSTRA- 


TION  AND  HYSTERIA.    In  one  12mo.  vol.  of  97  pages.   Cloth,  $1. 

pOLITZER  (ADAM).  A  TEXT-BOOK  OF  THE  EAR  AND  ITS  DIS- 
EASES. Translated  at  the  Author's  request  by  James  Patterson 
Cassells,  M.D.,  F.F.P.S.  In  one  handsome  octavo  volume  of  800 
pages,  with  257  original  illustrations.    Cloth,  $5  50. 

pOWER  (HENRY).  HUMAN  PHYSIOLOGY.  Second  edition.  In 
one  12mo.  volume  of  396  pages,  with  47  illustrations.  Cloth,  $1  50. 
See  Students'"  Series  of  Manuals,  page  14. 

pURDY  ON  BRIGHT  S  DISEASE  AND  ALLIED  AFFECTIONS  OF 

■*-      THE  KIDNEY.    Octavo,  288  pp.,  with  18  handsome  illus.    Cloth,  $2. 

"DALFE  (CHARLES  H.)  CLINICAL  CHEMISTRY.  In  one  12mo. 
volume  of  314  pages,  with  16  illustrations.  Cloth,  $1  50.  See 
St7idents'  Series  of  Manuals,  page  14. 

pAMSBOTHAM   (FRANCIS   H.)     THE  PRINCIPLES  AND  PRAC- 

-"*  TICE  OF  OBSTETRIC  MEDICINE  AND  SURGERY.  Inoneim- 
perial  octavo  volume  of  640  pages,  with  64  plates,  besides  numerous 
woodcuts  in  the  text.     Strongly  bound  in  leather,  $7. 

pEMSEN(IRA).  THE  PRINCIPLES  OF  CHEMISTRY.  New  (third) 
edition,  thoroughly  revised,  and  much  enlarged.  In  one  12mo. 
volume  of  318  pages.     Cloth,  $2. 

pEYNOLDS  (J.RUSSELL).  A  SYSTEM  OF  MEDICINE.  Edited, 
with  Notes  and  Additions,  by  Henry  Hartshorne,  MD.  In  three 
larga  8vo.  vols.,  containing  3056  closely  printed  double-columned 
pages,  with  317  illustrations.  Per  volume,  cloth,  $5  ;  leather,  $6  ; 
very  handsome  half  Russia,  $6  50.     For  sale  by  subscription  only 

•RICHARDSON  (BENJAMIN  W.)  PREVENTIVE  MEDICINE.  In 
one  octa         '    .  of  729  pp.     Clo  ,  $4;  leather,  $5. 

ROBERTS  (JOHN  B.)  AND  MORTON  (THOS.  S.  K.)     THE   PRIN- 
CIPLES    AND   PRACTICE    OF    MODERN    SURGERY.     In  one 
ociavo  volume  of  about  500  pages,  fully  illustrated.     Preparing. 
■pOBERTS  (JOHN  B.)     THE  COMPEND  OF  ANATOxMY.     Far  use  in 
•"     the  Dissecting  Room  and  in   preparing  for  Examinations.     In  one 
16mo.  volume  of  196  pages.     Limp  cloth,  75  cents. 


E 


LEA  BROTHERS  &  CO.'S  PUBLICATIONS.  13 

•pOBERTS  (WILLIAM).   A  PRACTICAL  TREATISE  ON  URINARY 
^    AND  RENAL  DISEASES,  INCLUDING  URINARY  DEPOSITS. 

Fourth  American,  from  the  fourth  London  edition.     In  one  very 

handsome  8vo.  vol.  of  609  pages,  with  81  illustrations.    Cloth,  $3  50. 
■pOBERTSON  (J.  McGREGOR).     PHYSIOLOGICAL   PHYSICS.     In 

one  ]2mo.  volume  of  537  pages,  with  219  illustrations.    Cloth,  $2  00. 

See  Students^  Series  of  Manuals,  p.  14. 
OSS    (JAMES).      A    HANDBOOK   OF   THE    DISEASES   OF    THE 

NERVOUS  SYSTEM.  In  one  handsome  octavo  volume  of  726  pages, 

with  184  illustrations.     Cloth,  $4  50  ;  leather,  $5  50. 
LAVAGE    (GEORGE   H)      INSANITY  AND    ALLIED  NEUROSES, 
*^     PRACTICAL  AND  CLINICAL.    In  one  12mo.  volume  of  551  pages, 

with  18  typical  illustrations.     Cloth,  $2  00.     See  Series  of  Clinical 

Manuals,  p    13. 

S CHAFER  (EDWARD  A.)  THE  ESSENTIALS  OF  HISTOLOGY, 
DESCRIPTIVE  AND  PRACTICAL.  For  the  use  of  Students.  In 
one  handsome  octavo  volume  of  246  pages,  with  281  illustrations. 
Cloth,  $2  25. 

SCHMITZ  AND  ZUMPT'S  CLASSICAL  SERIES.  In  royal  18mo. 
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SALLUST.     Cloth,  60cents;  half  bound,  70  cents. 
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VIRGIL.     Cloth,  85  cents;  half  bound,  $1. 
CURTIUS.     Cloth,  80  cents;  half  bound,  90  cents. 

SCHOEDLER (FREDERICK)  AND  MEDLOCK (HENRY).  WONDERS 
OF  NATURE.  An  elementary  introduction  to  the  Sciences  of 
Physics,  Astronomy,  Chemistry,  Mineralogy,  Geology ,  Botany,  Zool- 
ogy  and  Physiology.    In  one  8vo.  vol.,  with  679  illus.    Cloth,  $3. 

SCHREIBER  (JOSEPH).  A  MANUAL  OF  TREATMENT  BY  MAS- 
SAGE AND  METHODICAL  MUSCLE  EXERCISE.  Translated 
by  Walter  Mendelson,  M.D.,  of  New  York.  In  one  handsome  octavo 
volume  of  274    pages,  with   117  fine   engravings.      Cloth,    $2  75. 

SEILER  (CARL).  A  HANDBOOK  OF  DIAGNOSIS  AND  TREAT- 
MENT  OF  DISEASES  OF  THE  THROAT  AND  NASAL  CAV- 
ITIES. New  (3d)  edition.  In  one  very  handsome  12ino.  volume 
of  373  pages,  with  101  illustrations,  and  2  beautifully  colored  plates. 
Cloth,  $2  25. 

SENN  (NICHOLAS).     SURGICAL  BACTERIOLOGY.     In  one  hand- 
some octavo  volume  of  259  pages,  with  13  plates,  9  of  which  are 
colored.     Cloth,  $1  75.     Just  ready. 
OEEIES  OF  CLINICAL  MANUALS      A  series  of  authoritative  mono- 
►J     graphs  on  important  clinical  subjects,  in  12mo.  volumes  of  about  550 
pages,  well    illustrated.      The  following  volumes    are  now   ready  : 
Ball  on  the  Rectum  and  Anus,  $2  25  ;  Carter  and  Frost's  Ophthalmic 
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of  the  Joints  (1^2);  Morrison  Surgical  Diseases  of  the  Kidney  ($2  25); 
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tion ($2).     The  following  are  in  press:  Broadbent  on  the  Pulse; 
Lucas  on  Diseases  of  the  Urethra. 
For  separate  notices,  see  under  various  authors'  names. 

SIMON  (W.)  MANUAL  OF  CHEMISTRY.  A  Guide  to  Lectures 
and  Laboratory  work  for  Beginners  in  Chemistry.  A  Text-book 
specially  adapted  for  Students  of  Pharmacy  and  Medicine.  New 
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34  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

gKEY  (FREDERIC  C.)    OPERATIVE  SURGERY      In  one  8vo.  vol. 

^     of  661  pages,  with  81  woodcuts.     Cloth,  iS;3  25. 

gLADE(D.D.)  DIPHTHERIA;  ITS  NATURE  AND  TREATMENT. 
Second  edition.     In  one  royal  12mo.  vol.  pp.  158.     Cloth,  $125. 

gMITH  (EDWARD),  CONSUMPTION;  ITS  EARLY  AND  REME- 
DIABLE STAGES.     In  one  8vo.  vol.  of  253  pp.     Cloth,  $2  25. 

OMITH  (J.LEWIS).    A  TREATISE  ON  THE  DISEASES  OF  IN- 

^  FANCY  AND  CHILDHOOD.  Sixth  edit  ion, revised  and  enlarged. 
In  one  large  Svo.  volume  of  867  pages,  with40  illustrations.  Cloth, 
$4  50  ;  leather,  $5  50. 

OMITH  (STEPHEN).  OPERATIVE  SURGERY.  New  (second)  and 
thoroughly  revised  edition.  In  one  very  handsome  Svo.  volume, 
of  892  pages,  with  1005  illustrations.     Cloth,  S4 ;  leather,  $b. 

OTILIE  (ALFRED).      CHOLERA,  ITS  ORIGIN,  HISTORY,  CAUSA- 

'"^  TION,  SYMPTOMS,  LESIONS,  PREVENTION  AND  TREAT- 
MENT.  In  one  handsome  12rao.  volume  of  163  pages,  with  a  chart 
showing  routes  of  previous  epidemics.     Cloth,  $1  25. 

nilLLE  (ALFRED).    THERAPEUTICS  AND  MATERIA  MEDICA. 

^  Fourth  revised  edition.  In  two  handsome  octavo  volumes  of  1936 
pages.    Cloth, $10;  leather, $12;  very  handsome  half  Russia,  $13. 

STILLE  (ALFRED)  AND  MAISCH  (JOHN  M  )  THE  NATIONAL 
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ognized in  the  latest  Pharmacopoeias  of  the  United  States,  Great 
Britain  and  Germany,  with  numerous  references  to  the  French 
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dix. In  one  magnificent  imperial  octavo  volume  of  1794  pages, 
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TIMSON  (LEWIS  A.)  A  TREATISE  ON  FRACTURES  AND 
DISLOCATIONS.  In  two  handsome  octavo  volumes.  Vol.  I.,  Frac 
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one    royal    12mo.  'volume    of  503   pages,    with    342    illustrations. 
Cloth,  $2  50. 

STUDENTS'  SERIES  OF  MANUALS.  A  series  of  fifteen  Manuals  by 
eminent  teachers  or  examiners.  The  volumes  are  pocket-size 
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3  volumes,  each  $2  00  ;  Bell's  Comparative  Physiology  and  Anatomy, 
$2  00;  Robertson's  Physiological  Physics,  $J  00  ;  Gould  s  Surgical 
Diagnosis,  $2  00;  Klein's  Elements  of  Histology  (3d  edition), 
$1  50;  Pepper's  Surgical  Pathology,  $2  00  ;  Treves'  Surgical  Ap- 
plied  Anatomy,  $2  00  ;  Power's  Human  Physiology,  second  edition, 
$1  50;  Ralfe's  Clinical  Chemistry,  $1  50;  and  Clarke  and  Lock- 
wood's  Dissector's  Manual,  $1  50.  The  following  is  in  press  :  Pep- 
per's Forensic  Medicine. 
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STURGES  (OCTAVIUS).  AN  INTRODUCTION  TO  THE  STUDY 
OF  CLINICAL   MEDICINE.     In  one  12mo.  vol.    Cloth,  $1  25. 


S' 


LEA  BROTHERS  &  CO  'S  PUBLICATIONS.  15 

TAIT  (LAWSON).  DISEASES  OF  WOMEN  AND  ABDOMINAL 
SURGERY.  Handsome  octavo  volume,  600  pages,  fully  illustrated. 
Pre])ari7tg. 

TANNER  (THOMAS  HAWKES) .  A  MANUAL  OF  CLINICAL  MEDl. 
CINE  AND  PHYSICAL  DIAGNOSIS.  Third  American  from  the 
second  revised  English  edition.  Edited  by  Tilbury  Fox,  M.  D.  In 
one  handsome  12mo.  volume  of  362  pp.,  with  illus.     Cloth,  $1  50. 

ON  THE  SIGNS  AND  DISEASES  OF  PREGNANCY.    From 

the  second  English  edition.     In  one  8vo.  volume  of  490  pages,  with 
four  colored  plates  and  numerous  woodcuts.     Cloth,  $4  25. 

TAYLOR  (ALFRED  S.)  MEDICAL  JURISPRUDENCE.  Eighth 
American    from    tenth  English   edition,    specially  revised  by  the 

Author.     Edited  by  John  J.  Reese,  M.D.     In   one  large  octavo 

volume  of  937  pages,  with  70  illustrations.     Cloth,  $6;  leather, 

$6. 
ON  POISONS  IN  RELATION  TO  MEDICINE  AND  MEDICAL 

JURISPRUDENCE.     Third  American  from  the  third  London  edi- 

tion.     In  one  octavo  volume  of  788  pages,  with  104  illustrations. 

Cloth,  $5  50;  leather,  $6  50. 
THE  PRINCIPLES  AND  PRACTICE  OF  MEDICAL  JU  RIS- 

PRUDENCE.     Third  ed.    In  two  handsome  8vo.  vols,  of  1416  pp., 

with  188  illustrations.     Cloth,  $10;  leather,  $12. 

TAYLOR  (ROBIRT  W.)-.  A  CLINICAL  ATLAS  OF  VENEREAL 
AND  SKIN  DISEASES.  Including  Diagnosis,  Prognosis,  and 
Treatment.  In  eight  large  folio  parts,  measuring  14  x  18  inches, 
and  comprising  213  beautiful  figures  on  58  fuil-pt'ge  chromo-litho- 
graphic  plates,  85  fine  engravings,  and  425  pages  of  text.  Com- 
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THE  PATHOLOGY  AND  TREATMENT  OF  VENEREAL  DIS- 
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very  handsome  8vo.  volume  of  about  900  pages,  with  about  150  en- 
gravings as  well  as  chromo-lithographic  plates.     Preparing. 

THOMAS  (T.  GAILLARD).  A  PRACTICAL  TREATISE  ON  THE 
DISEASES  OF  WOMEN.  Fifth  edition,  thoroughly  revised  and 
rewritten.  In  one  large  and  handsome  octavo  volume  of  810 
pages,  with  266  illustrations.  Cloth,  $5  ;  leather,  $6;  very  hand- 
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THOMPSON  (SIB  HENRY) .  CLINICAL  LECTURES  ON  DISEASES 
OF  THE  URINARY  ORGANS,  Second  and  revised  edition.  In 
one  octavo  volume  of  203  pages,  with  illustrations.    Cloth,  $2  25. 

THiKPSON    (SIR   HENRY).     THE    PATHOLOGY   AND  TREAT- 
MENr  OF  STRICTURE  OF  THE  URETHRA  AND  URINARY 
FISTUL.^.     From  the  third  English  edition.     In  one  octavo  vol- 
me  of  359  pages,  with  illustrations.     Cloth,  $3  50. 

TIDY  (CHARLES  MEYMOTT).  LEGAL  MEDICINE.  Volumes  I. 
and  II.  Two  imperial  octavo  volumes  containing  1193  pages,  with 
2  colored  plates.     Per  volume,  cloth,  $6;  leather,  $7. 

TODD  (ROBERT  BENTLEY) .  CLINICAL  LECTURES  ON  CERTAIN 
ACUTE  DISEASES.    In  one8vo.  vol.  of  320  pp.,  cloth,  $2  50. 
TREVES  (FREDERICK).    A  MANUAL  OF  SURGERY.    In  Treatises 
by  33  leading   surgeons.     Three   12mo.  volumes,  containing   1866 
pages,   with    213    engravings.     Price   per  set,    $6.     See    Students 
Series  of  Manuals,  p.  14. 

SURGICAL  APPLIED  ANATOMY.     In  one  12mo.  volume  of 

540  pages,  with  61  illustrations.     Cloth    $2  00.    See  Students' Series 
of  Ma?ii/als,  page  14. 

INTESTINAL  OBSTRUCTION.     In  one  12mo.  volume  of  522 

pages,  with  60  illustrations.     Cloth,  $2  00.     See  Series  of  Clinical 
Manuals^  p.  13. 


16  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

mUKE  (DANIEL  HACK) .  THE  INFLUENCE  OF  THE  MIND  UPON 
THE  BODY.  Second  edition.  In  one  handsome  8vo.  voL  of  467 
pages,  with  2  colored  plates.     Cloth,  $3. 

YAUGHAN  (VICTOR  C),  and  NOVY  (FBED'K  G.)  PTOMAINES 
*  AND  LEUCOMATNES.  OR  PUTREFACTIVE  AND  PHYSIO- 
LOGICAL ALKALOIDS.  In  one  handsome  12mo.  volume  of  311 
pages.     Cloth,  $1  75. 

VISITING  LIST.    THE  MEDICAL  NEWS  VISITING  LIST  for  1890. 
Thoroughly  revised.     48  pages  of  indispensable  data,  and  176  pages 
of  conveniently  ruled  and  classified  blanks  for  records.  Pocket,  pencil, 
catheter  scale,  and  erasable  tablet.     Three  styles :  Weekly  (dated, 
for   30   patients)  ;    Monthly    (undated),    and    Perpetual    (undated) 
Each  in  one  vol.,  price,  $1  25.     With  thumb-letter  index  for  quick 
use,  25  cents  extra.     Special  rates  to  advance- paying  subscribers  to 
The  Medical  News  or  The  American  Journal,  or  both.     See  p.  1. 
WALSHE  (W.  H.)     PRACTICAL  TREATISE  ON  THE  DISEASES 
'''    OF  THE  HEART  AND  GREAT  VESSELS.   3d  American  from  the 
3d  revised  London  edition.  In  one  8vo.  vol.  of420  pages.  Cloth,  $3. 
WATSON    (THOMAS).    LECTURES  ON  THE  PRINCIPLES  AND 
^ '    PRACTICE  OF  PHYSIC.    A  new  American  from  the  fifth  and  en- 
larged English  edition,  with  additions  by  H.  Hartshorne,  M.D.    In 
two  large  8vo.  vols,  of  1840  pp.,  with  190  cuts.    Clo.,$9;  lea., ^11. 
WELLS  (J.  SOELBERG).    A  TREATISE  ON  THE  DISEASES  OP 
"''    THE  EYE.    New  (fifth)  edition,  thoroughly  revised.     In  one  large 
and  handsome  octavo  vol.  of  aljoUt  800  pages,  with  colored  plates 
and  about  300  woodcuts,  as  well  as  selections  from  the  test-types 
of  Jaeger  and  Snellen. 
WEST  (CHARLES).     LECTURES  ON  THE  DISEASES  PECULIAR 
''    TO  WOMEN.    Third  American  from  the  third  English  edition.    In 
one  octavo  volume  of  543  pages.     Cloth,  $3  75  ;  leather,  $4  75. 

ON   SOME  DISORDERS   OF   THE    NERVOUS  SYSTEM   IN 

CHILDHOOD.  In  one  small  12mo.  vol.  of  127  pages.  Cloth,  $1. 
WILLIAMS  (CHARLES  J.  B.  and  C.  T.^  PULMONARY  CONSUMP- 
'*  TION:   ITS  NATURE,  VARIETIES   AND   TREATMENT.     In 

one  octavo  volume  of  303  pages.     Cloth,  $2  50. 
WILSON  (ERASMUS).     A  SYSTEM  OF  HUMAN  ANATOMY.     A 
new  and  revised  American  from  the  last  English  edition.    Illustrated 
with  397   engravings  on  wood.     In  one  handsome  octavo  volume 
of  616  pages.     Cloth,  $4;  leather,  $5. 

THE  STUDENT'S  BOOK  OF  CUTANEOUS  MEDICINE.    In 

one  handsome  royal  12mo.  vol.     Cloth,  $3  50. 
WINCKEL  ON  PATHOLOGY  AND  TREATMENT  OF  CHILDBED. 
With  additions  by  the  Author.    Translated  by  James  R.  Chadwick, 
A.M. ,  M.D.    In  one  handsome  8vo.  vol.  of  484  pages.    Cloth,  $4. 

WOHLER'S  OUTLINES  OF  ORGANIC  CHEMISTRY.  Translated 
from  the  8th  German  edition,  by  Ira  Remsen,  M.D.  In  one  12mo. 
volume  of  550  pages.    Cloth,  $3  00. 

W GODHEAD  (G.  SIMS).  PRACTICAL  PATHOLOGY.  A  Manual 
for  Students  and  Practitioners.  In  one  beautiful  octavo  vol.  of  497 
pages,  with  136  exquisitely  colored  illus.     Cloth,  $6. 

YEAR-BOOK  OF  TREATMENT  FOR  1889.  A  Comprehensive  and 
Critical  Review  for  Practitioners  of  Medicine.  In  contributions 
by  22  well-known  medical  writers.  12mo.;  349  pp.  Limp  cloth,  $1  25. 
For  special  rate  with  The  Medical  News  and  The  American  Journal 
of  the  Medical  Sciences,  see  page  1. 

YEAR-BOOK  OF  TREATMENT  FOR  1887.    Similar  to  above.    12mo., 
341  pages.     Limp  cloth,  $1  25. 
YEAR-BOOK  OF  TREATMENT  FOR  1886.   Similar  to  above.    12mo., 
320  pages.     Limp  cloth,  $8  25. 


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